CN102459204A

CN102459204A - Polycyclic antagonists of lysophosphatidic acid receptors

Info

Publication number: CN102459204A
Application number: CN2010800344199A
Authority: CN
Inventors: J.H.哈钦森; T.J.塞德斯; B.王; J.M.阿鲁达; J.R.罗普; T.帕尔
Original assignee: Amira Pharmaceuticals Inc
Current assignee: Amira Pharmaceuticals Inc
Priority date: 2009-06-03
Filing date: 2010-06-03
Publication date: 2012-05-16
Anticipated expiration: 2030-06-03
Also published as: US8273780B2; GB201009231D0; IL240749A0; KR101774722B1; EP2438048B1; EA020139B1; PT2438048E; GB2470833A8; PE20120936A1; IL216220A0; WO2010141768A2; EP2438048A4; AU2010256501B2; CA2764445C; JP2012528884A; WO2010141761A2; CO6480918A2; SG176112A1; AU2010256501A1; US8058300B2

Abstract

Described herein are compounds that are antagonists of lysophosphatidic receptor(s). Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such antagonists, alone and in combination with other compounds, for treating LPA-dependent or LPA-mediated conditions or diseases.

Description

Many rings antagonist of lpa receptor

The cross reference of related application

The denomination of invention that the application requires on June 3rd, 2009 to submit to is the rights and interests of the U.S. Provisional Patent Application 61/183,785 of " ANTAGONISTS OF LYSOPHOSPHATIDIC ACID RECEPTORS ", is incorporated herein the application as a reference.

Technical field

The application has described compound, has prepared method, the pharmaceutical composition that comprises said compound and the medicine of said compound, has reached said compounds for treating, prevention or diagnosis and one or more Ultrapole Ls (lysophosphatidic acid, the method for disease, obstacle or illness that LPA) acceptor is relevant used.

Background technology

Lysophospholipid is a film deutero-biological activity lipid medium.Lysophospholipid influence comprises propagation, breaks up, survives, moves, sticks, invasion and attack and morphogenetic elementary cell function.The many biological processess of these function effects, it includes but not limited to neural generation, blood vessel generation, wound healing, fibrosis, immunity and carcinogenesis.

Ultrapole L (LPA) is for show through specificity G-protein linked receptor (GPCR) group with autocrine and the acting lysophospholipid of paracrine mode.LPA is bonded to its homology GPCR (LPA ₁, LPA ₂, LPA ₃, LPA ₄, LPA ₅, LPA ₆) in the Kiwi signal transduction path to produce various biological respinses.The antagonist of finding the LPA acceptor is used to treat the acting disease of LPA, obstacle or illness.

Summary of the invention

In one aspect; The application provides the compound of formula (I); The medicine that it suppresses the physiologically active of Ultrapole L (LPA) and therefore wherein suppresses the disease that the physiologically active of LPA can effectively treat as treatment or prevention; The cause of disease of said disease such as the disease that relates to the LPA acceptor, disease or pathology relate to the disease of LPA acceptor, or the LPA acceptor disease relevant with at least a symptom of disease.

In one aspect, the compound of formula (I) is used to treat following disease: the fibrosis of organ (liver, kidney, lung, heart etc.), hepatopathy (acute hepatitis, chronic hepatitis, hepatic fibrosis, liver cirrhosis, portal hypertension, regeneration depletion, nonalcoholic fatty liver disease (NASH), hypohepatia, hepatic blood flow illness etc.), cell proliferation disorders (the aggressive transfer of cancer (solid tumor, solid tumor transfer, hemangiofibroma, myelomatosis, multiple myeloma, Kaposi sarcoma, white blood disease, lymphocytic leukemia (CLL) etc.) and cancer cells etc.), inflammatory diseases (psoriasis, ephrosis, pneumonia etc.), gastrointestinal tract disease (irritable bowel syndrome (IBS), inflammatory bowel (IBD), pancreas diacrisis etc.), kidney disease, the disease relevant with urinary tract (benign prostatic hyperplasia or with the symptom of nervous bladder disease-related, spinal cord knurl, protrusion of intervertebral disc, spinal stenosis, the inflammatory diseases, misnicturition, frequent micturition etc. of symptom, lower urinary tract disorders (lower urinary tract obstruction etc.), lower urinary tract derived from mellitus), pancreas disease, with abnormal vascular relevant disease (obstruction of artery etc.), scleroderma, the disease (cerebral infarction, hematencephalon etc.) of being correlated with brain, neuropathic pain, peripheral neurophaty etc., eye disease (the macula lutea degenerative change (AMD) of being correlated with the age, diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery cicatrization etc.) take place.In one aspect, the compound of formula (I) is used to treat fiber disease or illness.

In one aspect, the application has described compound, its pharmaceutical salts, solvolyte and the prodrug of formula (I).The compound of formula (I) is for being selected from LPA ₁, LPA ₂, LPA ₃, LPA ₄, LPA ₅And LPA ₆The LPA acceptor at least a antagonist.In one embodiment, the compound of formula (I) is LPA ₁Antagonist.In one embodiment, the compound of formula (I) is LPA ₁And/or LPA ₃Antagonist.In some embodiments, the compound of formula (I) is LPA ₁And/or LPA ₂Antagonist.In some embodiments, the compound of formula (I) is for being directed against the selective antagonist with respect at least a LPA acceptor of other LPA acceptor.In some embodiments, said selective antagonist is to LPA ₁Acceptor has selectivity.In some embodiments, said selective antagonist is to LPA ₂Acceptor has selectivity.In some embodiments, said selective antagonist is to LPA ₃Acceptor has selectivity.

The compound of formula (I) is used to treat is wherein known from experience the symptom of promotion disease, obstacle or illness or said disease, obstacle or the illness of progress through at least a LPA of LPA activation.In one aspect, the described method of the application, compound, pharmaceutical composition and medicine comprise the antagonist of one or more LPA acceptors.In one aspect, the described method of the application, compound, pharmaceutical composition and medicine comprise LPA ₁, LPA ₂Or LPA ₃Antagonist, or the combination of said antagonist.

In one aspect, the application provides the compound or pharmaceutically acceptable salt thereof of formula (I):

Formula (I)

Wherein

R ¹For-CO ₂H ,-CO ₂R ^D,-CN ,-C (=O) N (R ⁹) ₂,-C (=O) NHCH ₂CH ₂SO ₃H, or-C (=O) NHSO ₂R ¹⁰, tetrazyl, or 5-oxo-2,5-dihydro-[1,2,4] oxadiazoles-3-base; R ^DBe H or C ₁-C ₄Alkyl;

R ³Be H, C ₁-C ₄Alkyl, C ₃-C ₆Naphthenic base or C ₁-C ₄Fluoroalkyl;

R ⁴For-NR ⁷C (=O) OCH (R ⁸)-CY;

R ⁷Be H or C ₁-C ₄Alkyl;

R ⁸Be H, C ₁-C ₄Alkyl or C ₁-C ₄Fluoroalkyl;

CY is through replacement or without substituted C ₃-C ₆Naphthenic base, or through replacing or without substituted phenyl, being through substituted as if CY wherein, then CY is substituted with 1 or 2 R ^C

R ⁹Be H, C ₁-C ₆Alkyl, C ₁-C ₆Fluoroalkyl, C ₃-C ₆Naphthenic base, or through replacement or without substituted phenyl;

R ¹⁰Be C ₁-C ₆Alkyl, C ₁-C ₆Fluoroalkyl, C ₃-C ₆Naphthenic base, or through replacement or without substituted phenyl;

R ^A, R ^BAnd R ^CBe selected from independently of one another F, Cl, Br, I ,-CN ,-OH, C ₁-C ₄Alkyl, C ₁-C ₄Fluoroalkyl, C ₁-C ₄Fluoroalkyloxy, C ₁-C ₄Alkoxyl group and C ₁-C ₄Assorted alkyl;

M is 0,1 or 2; N is 1,2,3 or 4; P is 0,1 or 2.

In some embodiments, R ¹For-CO ₂H ,-CO ₂R ^D,-C (=O) NHSO ₂R ¹⁰Or tetrazyl; R ³Be H or C ₁-C ₄Alkyl; R ⁷Be H; R ⁸For H ,-CH ₃Or-CF ₃R ¹⁰Be C ₁-C ₆Alkyl or through replacing or without substituted phenyl; Each R ^ABe independently selected from F, Cl, Br, I ,-OH ,-CH ₃,-CF ₃,-OCF ₃And-OCH ₃Each R ^BBe independently selected from F, Cl, Br, I ,-OH ,-CH ₃,-CF ₃,-OCF ₃And-OCH ₃Each R ^CBe independently selected from F, Cl, Br, I ,-OH ,-CH ₃,-CF ₃,-OCF ₃And-OCH ₃M is 0 or 1; N is 1,2 or 3; P is 0 or 1.

In some embodiments, R ¹For-CO ₂H or-CO ₂R ^DR ^DFor H ,-CH ₃Or-CH ₂CH ₃R ³For H ,-CH ₃Or-CH ₂CH ₃R ⁴Be-NHC (=O) OCH (R ⁸)-CY; R ⁸For H or-CH ₃CY is through replacement or without substituted phenyl, and wherein if CY is through substituted phenyl, then this phenyl is substituted with 1 or 2 R ^C

In some embodiments, the compound of formula (I) has following structure:

In some embodiments, R ⁴For

CY is through replacement or without substituted phenyl, and wherein if CY is through substituted phenyl, then this phenyl is substituted with 1 or 2 R ^CR ^CFor F, Cl ,-OH ,-CH ₃,-CF ₃Or-OCH ₃N is 1.

In some embodiments, R ¹Be-C (=O) NHSO ₂R ¹⁰R ³For-CH ₃Or-CH ₂CH ₃R ⁸For H or-CH ₃R ¹⁰For-CH ₃Or-CH ₂CH ₃

In some embodiments, R ⁴Be-NHC (=O) OCH (CH ₃)-(is through replacement or without substituted phenyl); Wherein if phenyl is through substituted, then this phenyl is substituted with R ^CR ^CFor F, Cl ,-CH ₃Or CF ₃N is 1.

In some embodiments, R ⁴For

R ⁸For-CH ₃CY is through replacement or without substituted phenyl, and wherein if CY is through substituted phenyl, then this phenyl is substituted with 1 or 2 R ^CR ^CFor F, Cl ,-OH ,-CH ₃,-CF ₃Or-OCH ₃N is 1.

In some embodiments, CY is phenyl, 2-fluorophenyl, 3-fluorophenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 2-trifluoromethyl or 3-trifluoromethyl.

In some embodiments, the compound of formula (I) has following structure:

In some embodiments, R ¹For-CO ₂H; CY is phenyl, 2-fluorophenyl, 3-fluorophenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 2-trifluoromethyl or 3-trifluoromethyl.

In some embodiments, R ¹For-CO ₂H ,-CO ₂R ^D,-C (=O) NHSO ₂R ¹⁰, tetrazyl or 5-oxo-2,5-dihydro-[1,2,4] oxadiazoles-3-base.In some embodiments, R ¹For-CO ₂H ,-CO ₂R ^D,-C (=O) NHSO ₂R ¹⁰Or tetrazyl.In some embodiments, R ¹For-CO ₂H ,-CO ₂R ^DOr-C (=O) NHSO ₂R ¹⁰

In some embodiments, R ¹For-CO ₂H ,-CO ₂R ^D,-C (=O) NHSO ₂R ¹⁰, tetrazyl or 5-oxo-2,5-dihydro-[1,2,4] oxadiazoles-3-base; R ³Be H or C ₁-C ₄Alkyl; R ⁷Be H; R ⁸For H or-CH ₃R ¹⁰Be C ₁-C ₆Alkyl or through replacing or without substituted phenyl; CY is cyclopropyl, cyclobutyl, cyclopentyl, ring penta-1-thiazolinyl, 2-chlorine ring penta-1-thiazolinyl, cyclohexyl, hexamethylene-1-thiazolinyl, 2-chlorine hexamethylene-1-thiazolinyl, phenyl, 2-fluorophenyl, 2; 3-difluorophenyl, 2; 4-difluorophenyl, 2; 5-difluorophenyl, 2; 6-difluorophenyl, 2-chloro-phenyl-, 2; 6-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 2,4 dichloro benzene base, 2-hydroxy phenyl, 3-hydroxy phenyl, 4-hydroxy phenyl, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 2-fluoro-4-p-methoxy-phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 2-cyano-phenyl, 3-cyano-phenyl or 4-cyano-phenyl.

In some embodiments, each R ^ABe independently selected from F, Cl ,-CH ₃,-CF ₃,-OH ,-OCF ₃With-OCH ₃Each R ^BBe independently selected from F, Cl ,-CH ₃,-CF ₃,-OH ,-OCF ₃With-OCH ₃M is 0 or 1; P is 0 or 1.In some embodiments, n is 1.

The application contains the arbitrary combination of preceding text to the said group of a plurality of variablees.In whole specification sheets, select its group and substituting group so that steady component and compound to be provided by those skilled in the art.

In one aspect, the present invention provides compound given among table 1, table 2, Fig. 1, Fig. 2, Fig. 3, Fig. 4 and Fig. 5.

The compound of formula (I) is the antagonist of at least a LPA acceptor.In some embodiments, the compound of formula (I) is LPA ₁Antagonist.In some embodiments, the compound of formula (I) is LPA ₂Antagonist.In some embodiments, the compound of formula (I) is LPA ₃Antagonist.

In some embodiments, the application provides the compound of active metabolite, tautomer, solvolyte, pharmaceutical salts or prodrug of the compound of the formula of being selected from (I).

In some embodiments, the application provides pharmaceutical composition, and it comprises the compound of the formula (I) of treating significant quantity.In some embodiments, said pharmaceutical composition also contains at least a medicinal inert composition.

In some embodiments, the application provides pharmaceutical composition, and it comprises compound or its medicinal pharmaceutical salts, and at least a medicinal inert composition of the formula (I) of treating significant quantity.In one aspect, said pharmaceutical composition is used for intravenous injection, subcutaneous injection, oral administration, suction, intranasal administration, topical, dosing eyes or ear's administration by preparation.In some embodiments, this pharmaceutical composition is tablet, pill, capsule, liquid, inhalation, nasal spray solution, suppository, suspensoid, gelifying agent, colloid, dispersion agent, suspensoid, solution, emulsion, ointment, lotion, eye drops or ear drop.

In some embodiments, said pharmaceutical composition further comprises one or more additional procedures promoting agents except that the compound of formula (I).

In some embodiments, the application provides the method that comprises the compound of the human Medicine-feeding type (I) of disease or the illness of suffering from LPA dependency or LPA mediation.In some embodiments, to this mankind's administration one or more additional procedures promoting agents except that the compound of formula (I).In some embodiments, this method further comprises administration one or more additional procedures promoting agents except that the compound of formula (I).

In some embodiments, one or more additional procedures promoting agents except that the compound of formula (I) are selected from: cortin, immunosuppressor, anodyne, carcinostatic agent, antiphlogistic drug, chemokine receptor anagonists, bronchodilator, leukotrienes receptor antagonist, leukotrienes form suppressor factor, monoacylglycerol kinase suppressor factor, phospholipase A ₁Suppressor factor, phospholipase A ₂Suppressor factor, and Lysophospholipase D (lysoPLD) suppressor factor, autocrine motility factor suppressor factor, Decongestant, antihistaminic agent, mucolytic agent, anticholinergic, antitussive, expectorant and β-2 agonist.

The compound that is formula (I) on the other hand promotes the purposes in disease, obstacle or the illness of pathology and/or symptom of disease or illness in the activity of wherein at least a LPA acceptor of treatment.In an embodiment aspect this, the LPA acceptor is selected from LPA ₁, LPA ₂, LPA ₃, LPA ₄, LPA ₅And LPA ₆In some embodiments, the LPA acceptor is LPA ₁Or LPA ₂Or LPA ₃In some embodiments, this disease or illness are the disease of the application regulation or in the illness any.

The application also provides the method for the physiologically active that suppresses the LPA in the Mammals, and it comprises to the compound of the formula (I) of the Mammals drug treatment significant quantity that needs are arranged or its medicinal pharmaceutical salts.

An aspect is treatment or prevents mammiferous LPA dependency or the disease of LPA mediation or the method for illness that it comprises the compound of the formula (I) of drug treatment significant quantity.

In one aspect, disease or the illness of said LPA dependency or the LPA mediation fibrosis, cicatrization, hepatopathy, dermatology illness, cancer, cardiovascular disorder, respiratory disease or the illness that include but not limited to organ or tissue, inflammatory diseases, gastrointestinal tract disease, kidney disease, the disease relevant, inflammatory diseases, misnicturition, frequent micturition, pancreas disease, obstruction of artery, cerebral infarction, hematencephalon, pain, peripheral neurophaty and the fibromyalgia of lower urinary tract with urinary tract.

In some embodiments, the disease or the illness of said LPA dependency or LPA mediation are selected from idiopathic pulmonary fibrosis; The substantive tuberculosis of other diffusivity of different pathogenies comprises fibrosis, granulomatosis (sarcoidosis, hypersensitivity pneumonitis), collagen vascular disease, pulmonary alveolar proteinosis, Langerhans (langerhans) cell granulomatosis, LAM, the genetic diseases (Theo Hermans Ji-Pu De clarke (Hermansky-Pudlak) syndrome, tuberous sclerosis, multiple neurofibromatosis, metabolic storage illness, family's interstitial lung disease) of iatrogenic drug-induced fibrosis, occupation and/or ambient induced; Radiation induced fibrosis; Chronic obstructive pulmonary disease (COPD); Scleroderma; The pulmonary fibrosis that bleomycin (bleomycin) brings out; Chronic asthma; Silicosis; The pulmonary fibrosis of Induced by Asbestos; Adult respiratory distress syndrome (ARDS); Renal fibrosis; The uriniferous tubules interstitial fibrosis; Glomerulonephritis; Focal segmental glomerulosclerosis; IgA nephropathy; Hypertension; Alport syndrome; The intestines fibrosis; Hepatic fibrosis; Liver cirrhosis; The hepatic fibrosis that alcohol brings out; Drugs/drug-induced hepatic fibrosis; Hemochromatosis; Nonalcoholic fatty liver disease (NASH); Bile duct injury; Primary biliary cirrhosis; The hepatic fibrosis of infection-induced; Viral-induced hepatic fibrosis; And autoimmune hepatitis; Corneal scar forms; Hypertrophic cicatrix forms; Dupuytren disease (Dupuytren disease), keloid, fibrosis of skin; The skin scleroderma; Spinal injury/fibrosis; Myelofibrosis; Vascular restenosis; Atherosclerosis; Arteriosclerosis; Wei Genashi (the granulomatosis of Wegener ' s); Cavernitis,fibrous (Peyronie ' s disease), lymphocytic leukemia, metastases, transplant organ repulsion, endometriosis, hyaline membrane disease of newborn and neuropathic pain.

An aspect is for treating or prevent the method for mammalian cancer, and it comprises to the compound of the formula (I) of the Mammals drug treatment significant quantity that needs are arranged or its medicinal pharmaceutical salts.

An aspect is for treating or prevent the method for mammalian hair fiberization, and it comprises to the compound of the formula (I) of the Mammals drug treatment significant quantity that needs are arranged or its medicinal pharmaceutical salts.

An aspect is for treating or prevent the method for the following disease of Mammals: pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute injury of kidney, chronic nephropathy, hepatic fibrosis, fibrosis of skin, intestines fibrosis, breast cancer, carcinoma of the pancreas, ovarian cancer, prostate cancer, glioblastoma, osteocarcinoma, colorectal carcinoma, intestinal cancer, head and neck cancer, melanoma, multiple myeloma, lymphocytic leukemia, cancer pain, metastases, transplant organ repulsion, scleroderma, eye fibrosis, AMD (AMD), diabetic retinopathy, collagen vascular diseases, atherosclerosis, Raynaud's phenomenon (Raynaud ' s phenomenon) or neuropathic pain, it comprises to the compound of the formula (I) of the Mammals drug treatment significant quantity that needs are arranged or its medicinal pharmaceutical salts.

In one aspect, the application provides treatment or the Fibrotic method of prevention mammalian organs, and it comprises to the compound of the formula (I) of the Mammals drug treatment significant quantity that needs are arranged or its medicinal pharmaceutical salts.In some embodiments, said organ fibrosis comprises pulmonary fibrosis, renal fibrosis or hepatic fibrosis.

In one aspect, the application provides the method for improving the Mammals pulmonary function, and it comprises to the compound of the formula (I) of the Mammals drug treatment significant quantity that needs are arranged or its medicinal pharmaceutical salts.In one aspect, said Mammals has been diagnosed as and has suffered from pulmonary fibrosis.

In one aspect, the compound that the application disclosed is used to treat mammiferous idiopathic pulmonary fibrosis (ordinary property interstitial pneumonia).

In one aspect, the compound that the application disclosed is used to treat Raynaud's phenomenon.Raynaud's phenomenon comprise raynaud's disease (wherein this phenomenon is the special property of sending out) and Raynaud syndrome (wherein this phenomenon is caused by some other stimulating factor (instigating factor)) the two.

In some embodiments, the compound that the application disclosed is used to treat the substantive interstitial lung disease of mammiferous dispersivity: iatrogenic drug-induced tuberculosis, occupation/environment property tuberculosis (farmer lung), granulomatosis (sarcoidosis, hypersensitivity pneumonitis), collagen vascular disease (scleroderma and other), pulmonary alveolar proteinosis, langerhans cell granulomatosis, LAM, Hermansky Pudlak syndrome, tuberous sclerosis, multiple neurofibromatosis, metabolic storage illness, family's interstitial lung disease.

In some embodiments, the compound that the application disclosed is used to treat fibrosis after the mammiferous transplanting relevant with chronic rejection: the bronchiolitis obliterans of lung transplantation.

In some embodiments, the compound that the application disclosed is used to treat the mammalian skin fibrosis: skin scleroderma, dupuytren disease, keloid.

In one aspect, the compound that the application disclosed is used to treat the mammiferous hepatic fibrosis that has or do not have liver cirrhosis: drugs/drug-induced hepatic fibrosis (hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis B virus, hepatitis C virus (HCV)), non-alcoholic hepatopathy (NASH), metabolic and autoimmune disease.

In one aspect, the compound that the application disclosed is used to treat mammiferous renal fibrosis: uriniferous tubules interstitial fibrosis, glomerular sclerosis.

Relate to other embodiment that also comprises at least a additional agents of administration the above-mentioned aspect of treating LPA dependence disease or illness the compound arbitrarily for the structure that has formula (I) except that administration.In each embodiment, with random order (comprising simultaneously) each medicine of administration.

In the embodiment that the application disclosed arbitrarily, said Mammals is human.

In some embodiments, the compound administration that the application provided is human.In some embodiments, the compound oral administration that the application provided is human.

In some embodiments, the compound that the application provided is as the antagonist of at least a LPA acceptor.In some embodiments, the compound that the application provided is used to suppress the active of at least a LPA acceptor or is used to treat to benefit from active disease or the illness that suppresses at least a LPA acceptor.In one aspect, said LPA acceptor is LPA ₁

In other embodiments, the compound that the application provided is used for preparation and is used to suppress LPA ₁Active medicine.

Can make other purpose, characteristic and the advantage of the said compound of the application, method and composition become obvious by following detailed description.Yet; Indicate specific embodiments although it should be understood that said detailed description and specific embodiment; But only provide with the example description mode, this is because the various variations and the modification that are covered by in purport of the present invention and the scope can become obvious for a person skilled in the art through this detailed description.

Description of drawings

Fig. 1: the Illustrative embodiment of the said compound of the application.

Fig. 2: the Illustrative embodiment of the said compound of the application.

Fig. 3: the Illustrative embodiment of the said compound of the application.

Fig. 4: the Illustrative embodiment of the said compound of the application.

Fig. 5: the Illustrative embodiment of the said compound of the application.

Embodiment

Lysophospholipid (such as Ultrapole L (LPA)) influence comprises cell proliferation, differentiation, survival, moves, sticks, invasion and attack and morphogenetic elementary cell function.The many biological processess of these function effects, it comprises neural generation, blood vessel generation, wound healing, immunity and carcinogenesis.

LPA works with autocrine and paracrine mode through specificity G-protein linked receptor (GPCR) group.LPA is bonded to its homology GPCR (LPA ₁, LPA ₂, LPA ₃, LPA ₄, LPA ₅, LPA ₆) in the Kiwi signal transduction path to produce various biological respinses.

LPA has the biological effector molecule effect; And have multiple physiological action (such as but be not limited to; Effect to blood pressure, platelet activation and smooth muscle contraction), and various cytological effects (it comprise cell growth, cell rounding, aixs cylinder shrink, and Actin muscle stress fiber form and cell migration).The effect of LPA is mainly the mediation acceptor.

Can mediate a series of downstream signal cascades with LPA activation LPA acceptor amplifies.Actual approach and show that terminal point depends on a large amount of variablees, it comprises expression level, and the LPA concentration of acceptor use, cell type, acceptor or signal conductive protein.Several LPA receptor subtypes of nearly all mammalian cell, tissue and organ co expression, it indicates the LPA acceptor with the cooperative mode conducted signal.LPA ₁, LPA ₂And LPA ₃Share the homoamino acid sequence similarity.

The many critical functions of LPA regulation and control inoblast in wound healing comprise propagation, migration, differentiation and contraction.In wound healing, need fibroblast proliferation to fill open wound.On the contrary, Fibrotic strong propagation and the accumulation that is characterised in that myofibroblast, synthetic energetically ECM of said myofibroblast and proinflammatory cytokine.LPA can increase or suppress the propagation of cell type important in the wound healing.

Tissue injury causes host's wound healing reaction of a series of complicacies; If success, then these reacting recovery healthy tissues structure and functions.If failure, then these reactions can cause tissue fibrosis and afunction.

Many muscular dystrophy are characterised in that carrying out property weak and muscle tissue atrophy and extensive fibrosis.Having shown that the myoblastic LPA that is cultivated handles can bring out IGFBP-rP2 (CTGF) and significantly express.Subsequently, CTGF brings out collagen, fibronectin and integrin expression and brings out these sarcoplasts and dedifferente.Utilize LPA to handle that various cell types can bring out reappearing of CTGF and high level brings out.CTGF is short fibrosis cytokine, and it is at TGF β downstream conducted signal and parallelly connected with TGF β.

LPA and LPA ₁In pulmonary fibrosis, play crucial pathogenic effects.Inoblast chemical inhibitor activity plays an important role in the patient's who suffers from pulmonary fibrosis lung.LPA ₁The short fibrosis effect of-receptor for stimulating is passed through LPA ₁The inoblast of-receptor-mediated vascular leakage and increase is raised and explains, the two is short fibrosis incident.LPA-LPA ₁Approach plays migration of mediation inoblast and vascular leakage in IPF.Net result is for characterizing the unusual agglutination of this fibrosis illness.

The LPA-LPA2 approach impels the TGF-beta pathway activation in the pulmonary fibrosis.In some embodiments, the effect that suppresses the compound exhibits treatment pulmonary fibrosis of LPA2.In some embodiments, suppress the two compound of LPA1 and LPA2 and compare the effect that shows the treatment pulmonary fibrosis that improves with the compound that only suppresses LPA1 or LPA2.

LPA and LPA ₁Participate in the pathogeny of renal fibrosis.Make LPA ₁Invalid (the LPA of acceptor ₁(-/-)) mouse in, the development of renal fibrosis significantly weakens.UUO (UUO with LPA receptor antagonist Ki16425 treatment; The animal model of renal fibrosis) mouse and LPA ₁(-/-) mouse is very similar.

LPA is relevant with hepatopathy and fibrosis.Strengthen in the relevant liver damage animal model at hepatitis and with fibrosis, blood plasma LPA level and serum autotoxin raise.LPA also regulates and control hepatocyte function.LPA ₁And LPA ₂Acceptor stimulates the migration of liver myofibroblast through expression of Mouse Liver stellate cell and LPA.

LPA participates in the wound healing in the eye.LPA ₁And LPA ₃Acceptor can detect and LPA in normal rabbit corneal epithelial cell, corneal cell and endotheliocyte ₁And LPA ₃Be expressed in the corneal epithelial cell after the damage and strengthen.

LPA is present in aqueous humor and the lacrimal gland fluid of lagophthalmos and these levels increase in the rabbit corneal damage model.

The Actin muscle that LPA brings out in rabbit corneal endotheliocyte and the epithelial cell stress form and promote to shrink the cornea inoblast by fiber.LPA also stimulates the propagation of human retina pigment epithelial cell.

LPA is relevant with myocardial infarction and cardiac fibrosis.The propagation of increase and LPA stimulation in rats cardiac fibroblast and collagen produce (fibrosis) among the patient of serum LPA level after myocardial infarction (MI).LPA1 and LPA3 acceptor are all expressed at the human heart tissue camber.

In one aspect, the compound of formula (I) is used for treatment or prevents mammiferous fibrosis.In one aspect, the compound of formula (I) fibrosis that is used to treat or prevent mammiferous organ or tissue.

The used term of the application " fibrosis " or " fibrosis illness " are meant with the unusual accumulation of cell and/or fibronectin and/or collagen and/or the inoblast of increase raises relevant illness, and includes but not limited to the fibrosis of indivedual organ or tissues (such as heart, kidney, liver, joint, lung, pleura, peritoneal tissues, skin, cornea, retina, muscle skeleton and digestive tube).

Relating to Fibrotic exemplary disease, obstacle or illness includes but not limited to: the tuberculosis relevant with fibrosis; For example, the lung of idiopathic pulmonary fibrosis, the pulmonary fibrosis that is secondary to SIDA (such as rheumatoid arthritis, scleroderma, lupus), CFA, radiation induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, chronic asthma, silicosis, Induced by Asbestos or fibrosis of pleura, acute lung injury and acute respiratory distress (comprising acute respiratory distress that bacterial pneumonia brings out, wound is that bring out, that virus pneumonia is brought out, respirator brings out, that non-lung septicemia is brought out and that suction is brought out); The chronic nephropathy relevant (renal fibrosis) with damage/fibrosis; For example, be secondary to glomerulonephritis, mellitus, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allograft and the Alport syndrome of SIDA (such as lupus and scleroderma); The intestines fibrosis, for example, scleroderma and radiation induced intestines fibrosis; Hepatic fibrosis; For example; The hepatic fibrosis that liver cirrhosis, alcohol bring out, nonalcoholic fatty liver disease (NASH), bile duct injury, primary biliary cirrhosis, infection or viral-induced hepatic fibrosis (for example, chronic HCV infection), and autoimmune hepatitis; The neck fibrosis, for example, radiation induced neck fibrosis; Corneal scar forms, and for example, the corneal scar of LASIK (laser cornea original position attrition), corneoplasty and trabeculectomy forms; Hypertrophic cicatrix forms and keloid, for example, and hypertrophic cicatrix formation and keloid that burn brings out or performs the operation; And other fiber disease, for example, sarcoidosis, scleroderma, Spinal injury/fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegner granulomatosis, mixed connective tissue disease and cavernitis,fibrous.

In one aspect, a kind of Mammals that suffers from following non-restrictive illustrative disease, obstacle or the illness can be benefited from the therapy with the compound of formula (I): the formation of atherosclerosis, thrombosis, heart trouble, vasculitis, scar tissue, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, lung inflammation, intestinal adhesion, bladder fibrosis and urocystitis, nasal meatus fibrosis, sinusitis paranasal sinusitis, by the inflammation of neutrophilic granulocyte mediation, and by the fibrosis of inoblast mediation.

In one aspect, the compound of formula (I) is used to treat the mammalian skin disease.Said tetter includes but not limited to the proliferative or the inflammatory conditions of skin, such as atopic dermatitis, bleb illness, collagen disease, psoriasis, psoriasis damage, dermatitis, contact dermatitis, eczema, urticaria, acne erythematosa, wound healing, cicatrization, hypertrophic cicatrix formation, keloid, mucocutaneous lymphnode syndrome (Kawasaki Disease), acne erythematosa, house Glenn-Larsen (Sjogren-Larsso) syndrome, urticaria.

LPA discharges after tissue injury.LPA ₁In causing neuropathic pain, work.In one aspect, the compound of formula (I) is used to treat mammiferous pain.In one aspect, this pain is acute pain or chronic pain.On the other hand, this pain is neuropathic pain.On the other hand, this pain is cancer pain.In one aspect, the compound of formula (I) is used to treat fibroplasia.

The conduction of Lysophospholipid Receptor signal is worked in the pathogeny of cancer.Ultrapole L (LPA) and G-protein linked receptor (GPCR) LPA thereof ₁, LPA ₂, and/or LPA ₃In the cancer development of some types, work.

LPA impels tumour to take place through the mobility and the aggressive that strengthen cell.LPA is relevant with the initiation or the progress of ovarian cancer.The LPA that has remarkable concentration (2-80 μ M) in the ascites of ovarian cancer patients.Compare with normal ovarian superficial epithelium cell, in ovarian cancer cell, also cross expression LPA acceptor (LPA2 and LPA3).LPA also initiation or the progress with prostate cancer, breast cancer, melanoma, head and neck cancer, intestinal cancer (colorectal carcinoma), thyroid carcinoma, glioblastoma and other cancer is relevant.

The migration and the invasion and attack of the receptor-mediated pancreatic cancer cell of LPA system: Ki16425 and LPA1-specific siRNA are blocked external migration effectively through the LPA of Pancreas cancer patients and peritoneal fluid (ascites) are replied; In addition, Ki16425 blocks high peritonaeum and shifts the invasion and attack that LPA brings out and ascites is brought out of pancreatic cancer cell system active people such as (, J.Biol.Chem., 279,6595-6605,2004) Yamada.

Colorectal cancer cell system shows LPA ₁The remarkable expression of mRNA and through cell migration and produce angiogenesis factor LPA is replied.The mistake of LPA acceptor is expressed in the pathogenesis of thyroid carcinoma and works.LPA ₃At first by prostate cancer cell clone, the ability of autocrine propagation of bringing out prostate cancer cell with LPA is consistent.

In many cancer types, LPA acts as a spur in cancer progression.LPA is by the prostate cancer cell generation and bring out its propagation.LPA is through LPA ₁The signal conduction is brought out human colon's cancer DLD1 cell proliferation, is moved, sticks, reaches the angiogenesis factor secretion.In other human colon's cancerous cell line (HT29 and WiDR), LPA strengthens the secretion of cell proliferation and angiogenesis factor.In other colon carcinoma cell line, LPA ₂And LPA ₃Receptor activation causes cell proliferation.LPA ₁Shift relevant people such as (, Proc.Natl.Acad.Sci USA, 103,9643-9648,2006) Boucharaba with bone.

In one aspect, the compound of formula (I) is used to treat cancer.In one aspect, the compound of formula (I) is used to treat pernicious and optimum proliferative disease.In one aspect, the compound of formula (I) is used to prevent or reduce the propagation of tumour cell; The invasion and attack of cancer, mesothelioma of pleura or peritoneal mesothelioma and transfer; Cancer pain; Bone shifts.An aspect is for treating the method for mammalian cancer, and this method comprises that to the compound of Mammals Medicine-feeding type (I) and second therapeutical agent wherein this second therapeutical agent is a carcinostatic agent.In some embodiments, also use radiation-therapy.

The type of cancer includes but not limited to be in the solid tumor (such as following solid tumor: bladder, intestines, brain, breast, uterine endometrium, heart, kidney, lung, Lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organ (Tiroidina), prostate gland, skin (melanoma or rodent cancer)) or the neoplastic hematologic disorder (such as white blood disease) of any stage of the disease that shifts or do not shift.

In one aspect, LPA is the promoting factor of the morbidity of respiratory disease.The proinflammatory of LPA comprises that degranulation, the smooth muscle cell of mastocyte shrink and cytokine is discharged by dendritic cell.LPA brings out IL-8 and is secreted by human bronchial epithelial cell.In the patient's who suffers from asthma, chronic obstructive pulmonary disease, sarcoidosis of lung and adult respiratory distress syndrome BAL fluid, find to increase the IL-8 of concentration and shown that respiratory inflammation and respiratory tract that Il-8 increases the weight of asthmatic patient reinvent.Shown that the IL-8 that LPA1, LPA2 and LPA3 acceptor all promote LPA to bring out produces.

Vivo medicine-feeding LPA can bring out the tracheae hyperergy, the infiltration of itch-scratch reaction, eosinophilic granulocyte and neutrophilic granulocyte and activation, blood vessel are reinvented, and nocuity flexor response.LPA also brings out histamine and is discharged by mouse and rat hypertrophy cell.In one aspect, LPA's act as through LPA ₁And/or LPA ₃Mediation.In one aspect, the compound of formula (I) is used to treat mammiferous various supersensitivity illness.In one aspect, the compound of formula (I) is used to treat mammiferous respiratory disease, obstacle or illness.In one aspect, the compound of formula (I) is used to treat mammiferous asthma.In one aspect, the compound of formula (I) is used to treat mammiferous chronic asthma.

The used term of the application " respiratory disease " is meant the disease of the organ (such as nose, throat, larynx, pharyngotympanic tube, tracheae, segmental bronchus, lung, relevant muscle (for example, diaphragm and intercostal thing) and nerve) that the influence participation is breathed.Respiratory disease includes but not limited to asthma; Adult respiratory distress syndrome and supersensitivity (exogenous) asthma; Nonallergic (endogenous) asthma; Acute serious asthma; Chronic asthma; Clinical asthma; Night asthma; The asthma that allergen brings out; ASA; The asthma of exercise induced; The carbonic acid gas hyperventilation; The Childhood ictal asthma; The ictal asthma of adulthood; Cough variant asthma; Occupational asthma; Steroid resistant asthma; Seasonal asthma; The pollinosis; The perennial allergic rhinitis; Chronic obstructive pulmonary disease (comprises chronic bronchitis or pulmonary emphysema; Pulmonary hypertension; Interstitial pulmonary fibrosis and/or respiratory inflammation and cystic fibrosis) and anoxic.

In one aspect, the application provides the compound of formula (I) treating or preventing the purposes in the mammiferous chronic obstructive pulmonary disease, and it comprises the compound at least a formula (I) of at least effective dosage of Mammals.In addition, chronic obstructive pulmonary disease includes but not limited to chronic bronchitis or pulmonary emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and/or respiratory inflammation and cystic fibrosis.

Neural system is LPA ₁The main position of expressing.In one aspect, the application provides the compound of formula (I), and it is used for treatment or prevention mammalian nervous system illness.The used term of the application " neurological conditions " includes but not limited to cognition dysfunction after alzheimer's disease, cerebral edema, cerebral ischemia, apoplexy, multiple sclerosis, DPN, Parkinson's disease, multiple sclerosis, retinal ischemia, the operation, migraine, peripheral nerve pathology/neuropathic pain, Spinal injury, cerebral edema and head injury.

Wound healing behind the ischemia injury, tissue growth and myocardial vascular take place to cause usually that blood vessel takes place by (vascular system by preexist forms new capillary bed).The coordination of peptide growth factor and lysophospholipid control vascular endothelial cell (VEC) and surrounding blood vessel smooth muscle cell (VSMC) is bred, moves, sticks, breaks up and is assembled.In one aspect, the process imbalance of mediation blood vessel generation can cause atherosclerosis, hypertension, tumor growth, rheumatoid arthritis and diabetic retinopathy.

In one aspect, the compound of formula (I) is used for treatment or prevents mammiferous cardiovascular disorder, and it includes but not limited to: irregular pulse (room property or ventricular arrhythmia or the two); Atherosclerosis and sequela thereof; Angina disease; Cardiac rhythm is not normal; Myocardial ischemia; Myocardial infarction; Heart or vascular aneurysms; Vasculitis, apoplexy; The periphery obstructive arteriopathy of limbs, organ or tissue; Reperfusion injury behind brain, heart, kidney or other organ or tissue's ischemic; Endotoxin induction, operation property or traumatic shock; Hypertension, valvular heart disease, heart failure, abnormal blood pressure; Shock; Vasoconstriction (comprising the vasoconstriction relevant) with migraine; Aberrant angiogenesis; Inflammation; The insufficiency that is limited to one organ or tissue.

In one aspect; The application provides the method for prevention or treatment vasoconstriction, atherosclerosis and sequela, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and apoplexy, and it comprises the compound of at least a formula (I) of at least effective dosage of Mammals or comprises the pharmaceutical composition or the medicine of the compound of formula (I).In some embodiments, the application provides the method for prevention or treatment Raynaud's phenomenon.

In one aspect, the application provides the method that reduces heart reperfusion injury after myocardial ischemia and/or the intracellular toxin apoplexy, and it comprises the compound at least a formula (I) of at least effective dosage of Mammals.

In one aspect, the application provides and reduces the method that the Mammals blood vessel shrinks, and it comprises the compound at least a formula (I) of at least effective dosage of Mammals.

In one aspect, the application provides the method that reduces or prevent the Mammals elevation of blood pressure, and it comprises the compound at least a formula (I) of at least effective dosage of Mammals.

LPA is relevant with inflammatory/immunological disease.In one aspect, the compound of formula (I) is used for treatment or prevents mammiferous inflammation.In one aspect, find LPA ₁And/or LPA ₃Antagonist can be used for treatment or prevent mammiferous inflammatory/immunological disease.

The instance of inflammatory/immunity illness comprises psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel, dermatitis, osteo-arthritis, asthma, inflammatory muscle disease, rhinallergosis, vaginitis, interstitial cystitis, scleroderma, eczema, allotransplantation or xenotransplantation (organ, marrow, stem cell, and other cell and tissue) transplant rejection, graft versus host disease, lupus erythematosus, inflammatory diseases, type i diabetes, pulmonary fibrosis, dermatomyositis, xerodermosteosis (Sjogren ' s syndrome), thyroiditis (for example, bridge this (Hashimoto ' s) and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrence hepatitis, primary biliary cirrhosis, anaphylaxis conjunctivitis and atopic dermatitis.

According to an aspect for when the disease of LPA dependency or LPA mediation or illness become obvious clinically; Treat said disease or illness, prevention, reverse, interrupt or slow down its progress; Or the method for the relevant or relevant symptom of the disease of treatment and LPA dependency or LPA mediation or illness, it is through the compound to Mammals Medicine-feeding type (I).In certain embodiments, the experimenter has suffered from the disease or the illness of LPA dependency or LPA mediation when administration, or is in the risk of disease or illness development of LPA dependency or LPA mediation.

Some aspect is for preventing or treat the method that eosinophilic granulocyte and/or basophilic granulocyte and/or dendritic cell and/or neutrophilic granulocyte and/or monocyte and/or T cell are raised, and it comprises the compound at least a formula (I) of at least effective dosage of Mammals.

Some aspect is the method for treatment urocystitis (comprise, for example, interstitial cystitis), and it comprises the compound at least a formula (I) of at least drug treatment significant quantity of Mammals.

According to an aspect, the said method of the application comprises through to the compound of the formula (I) of experimenter's drug treatment significant quantity and confirm whether the patient responds to treatment and diagnose or whether definite patient suffers from the disease or the illness of LPA dependency or LPA mediation.

In one aspect, the application provides compound, its pharmaceutical salts, medicinal prodrug and the medicinal solvent thing of formula (I), and it is at least a LPA acceptor (for example, LPA ₁, LPA ₂, LPA ₃) antagonist and be used to treat the illness of suffering from one or more LPA dependencys or LPA mediation or the patient of disease, said illness or disease include but not limited to pulmonary fibrosis, renal fibrosis, hepatic fibrosis, cicatrization, asthma, rhinitis, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, sacroiliitis, anaphylaxy, psoriasis, inflammatory bowel, adult respiratory distress syndrome, myocardial infarction, aneurysma, apoplexy, cancer, pain, proliferative disorders and inflammatory disorders.In some embodiments, LPA dependent conditions or disease comprise those illnesss or the disease that wherein exists and/or observe absolute or excessive relatively LPA.

Aspect above-mentioned arbitrarily, the disease or the illness of said LPA dependency or LPA mediation include but not limited to organ fibrosis, asthma, supersensitivity illness, chronic obstructive pulmonary disease, pulmonary hypertension, lung or fibrosis of pleura, peritonaeum fibrosis, sacroiliitis, anaphylaxy, cancer, cardiovascular disorder, adult respiratory distress syndrome, myocardial infarction, aneurysma, apoplexy and cancer.

In one aspect, the compound of formula (I) is used for improving the corneal sensitivity decline that is caused by operation on cornea (such as laser cornea original position attrition (LASIK) or cataract operation), the corneal sensitivity that is caused by corneal degeneration descends, reaches the dry eyes symptom that causes thus.

In one aspect; The application provides the compound of formula (I) treating or preventing mammiferous eye inflammation and anaphylaxis conjunctivitis, vernal keratoconjunctivitis, reaching the purposes in the papillary conjunctivitis, and it comprises the compound at least a formula (I) of at least effective dosage of Mammals.

In one aspect, the compound that the application provides formula (I) is in treatment or prevent mammiferously with the sjogren disease of xeropthalmus or the purposes in the inflammatory diseases, and it comprises the compound at least a formula (I) of at least effective dosage of Mammals.

In one aspect, LPA and LPA acceptor (for example, LPA ₁) participate in the pathogenesis of osteo-arthritis.In one aspect, the application provides the compound of formula (I) and is treating or preventing the purposes in the mammiferous osteo-arthritis, and it comprises the compound at least a formula (I) of at least effective dosage of Mammals.

In one aspect, LPA acceptor (for example, LPA ₁, LPA ₃) promote the pathogenesis of rheumatoid arthritis.In one aspect, the application provides the compound of formula (I) treating or preventing the purposes in the mammiferous rheumatoid arthritis, and it comprises the compound at least a formula (I) of at least effective dosage of Mammals.

In one aspect, LPA acceptor (for example, LPA ₁) the promotion lipogenesis.In one aspect, the application provides the compound of formula (I) in Mammals, to promote the purposes that fatty tissue forms, and it comprises the compound at least a formula (I) of at least effective dosage of Mammals.

Compound

In one aspect, the application provides the have formula compound or pharmaceutically acceptable salt thereof of structure of (I):

Formula (I)

Wherein

R ⁴For-NR ⁷C (=O) OCH (R ⁸)-CY;

R ⁷Be H or C ₁-C ₄Alkyl;

R ⁸Be H, C ₁-C ₄Alkyl or C ₁-C ₄Fluoroalkyl;

CY is through replacement or without substituted C ₃-C ₆Naphthenic base or warp replace or without substituted phenyl, wherein if CY is through substituted, then CY is substituted with 1 or 2 R ^C

M is 0,1 or 2; N is 1,2,3 or 4; P is 0,1 or 2.

For reaching all embodiments arbitrarily, substituting group is selected from listed alternate subgroup.For example, in some embodiments, R ¹For-CO ₂H or-CO ₂(R ^D).In some embodiments, R ^DFor H ,-CH ₃Or-CH ₂CH ₃In some embodiments, R ¹For-CO ₂H.In some embodiments, R ¹Be-C (=O) NHSO ₂R ¹⁰In some embodiments, R ¹Be the carboxylic acid bioisostere.

In some embodiments, R ³Be H or C ₁-C ₄Alkyl.In some embodiments, R ³Be C ₁-C ₄Alkyl.In some embodiments, R ³For H ,-CH ₃Or-CH ₂CH ₃In some embodiments, R ³For-CH ₃Or-CH ₂CH ₃In some embodiments, R ³For-CH ₃In some embodiments, R ³Be H.

In some embodiments, R ⁷Be H.

In some embodiments, R ⁸Be H, C ₁-C ₄Alkyl or C ₁-C ₄Fluoroalkyl.In some embodiments, R ⁸Be H.In some embodiments, R ⁸Be H or C ₁-C ₄Alkyl.In some embodiments, R ⁸For H ,-CH ₃Or-CF ₃In some embodiments, R ⁸For-CH ₃In some embodiments, R ⁸For-CH ₂CH ₃

In some embodiments, R ¹For-CO ₂H ,-CO ₂R ^D,-C (=O) NHSO ₂R ¹⁰Or tetrazyl; R ³Be C ₁-C ₄Alkyl; R ⁷Be H; R ⁸For H ,-CH ₃Or-CF ₃R ¹⁰Be C ₁-C ₆Alkyl or through replacing or without substituted phenyl; Each R ^ABe independently selected from F, Cl, Br, I ,-OH ,-CH ₃,-CF ₃,-OCF ₃And-OCH ₃Each R ^BBe independently selected from F, Cl, Br, I ,-OH ,-CH ₃,-CF ₃,-OCF ₃And-OCH ₃Each R ^CBe independently selected from F, Cl, Br, I ,-OH ,-CH ₃,-CF ₃,-OCF ₃And-OCH ₃M is 0 or 1; N is 1,2 or 3; P is 0 or 1.

In some embodiments, R ¹For-CO ₂H or-CO ₂R ^DR ^DFor H ,-CH ₃Or-CH ₂CH ₃R ³For-CH ₃Or-CH ₂CH ₃R ⁴Be-NHC (=O) OCH (R ⁸)-CY; R ⁸For H or-CH ₃CY is through replacement or without substituted phenyl, and wherein if CY is through substituted phenyl, then this phenyl is substituted with 1 or 2 R ^C

In some embodiments, the compound of formula (I) has following structure:

In some embodiments, R ⁴For

R ⁸For-CH ₃CY is through replacement or without substituted phenyl, and wherein if CY is through substituted phenyl, then this phenyl is substituted with 1 or 2 R ^CR ^CFor F, Cl ,-OH ,-CH ₃,-CF ₃Or-OCH ₃N is 1.In some embodiments, CY is without substituted phenyl.

In some embodiments; CY is cyclopropyl, cyclobutyl, cyclohexyl, 2-chlorine hexamethylene-1-thiazolinyl, phenyl, 2-fluorophenyl, 2; 3-difluorophenyl, 2; 4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chloro-phenyl-, 2; 6-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 2,4 dichloro benzene base, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 2-fluoro-4-p-methoxy-phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 2-cyano-phenyl, 3-cyano-phenyl or 4-cyano-phenyl.

In some embodiments; CY is cyclopropyl, cyclobutyl, cyclopentyl, ring penta-1-thiazolinyl, 2-chlorine ring penta-1-thiazolinyl, cyclohexyl, hexamethylene-1-thiazolinyl, 2-chlorine hexamethylene-1-thiazolinyl, phenyl, 2-fluorophenyl, 2; 3-difluorophenyl, 2; 4-difluorophenyl, 2; 5-difluorophenyl, 2; 6-difluorophenyl, 2-chloro-phenyl-, 2,6-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 2,4 dichloro benzene base, 2-hydroxy phenyl, 3-hydroxy phenyl, 4-hydroxy phenyl, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 2-fluoro-4-p-methoxy-phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 2-cyano-phenyl, 3-cyano-phenyl or 4-cyano-phenyl.

In some embodiments; CY is phenyl, 2-fluorophenyl, 2; 3-difluorophenyl, 2; 4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chloro-phenyl-, 2; 6-dichlorophenyl, 2,4 dichloro benzene base, 2-hydroxy phenyl, 3-hydroxy phenyl, 4-hydroxy phenyl, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 2-fluoro-4-p-methoxy-phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl or 4-aminomethyl phenyl.

In some embodiments, CY is phenyl, 2-fluorophenyl, 3-fluorophenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 2-trifluoromethyl or 3-trifluoromethyl.In some embodiments, CY is a phenyl.In some embodiments, CY is phenyl, 2-hydroxy phenyl, 3-hydroxy phenyl or 4-hydroxy phenyl.

In some embodiments, the compound of formula (I) has following structure:

In some embodiments, the compound of formula (I) has a kind of in the following structure:

In some embodiments, CY is C ₃-C ₆Naphthenic base, through replacing or without substituted phenyl; Wherein if CY is that then CY is substituted with R through substituted ^CR ^CFor F, Cl ,-CH ₃Or CF ₃In some embodiments, CY is C ₃-C ₆Naphthenic base.

In some embodiments, R ⁴Be-NHC (=O) OCH (R ⁸)-CY.In some embodiments, R ⁴Be-NHC (=O) OCH ₂-(cyclopropyl) ,-NHC (=O) OCH (CH ₃)-(cyclopropyl) ,-NHC (=O) OCH ₂-(through replace or without substituted phenyl) or-NHC (=O) OCH (CH ₃)-(is through replacement or without substituted phenyl); Wherein if CY is that then CY is substituted with R through substituted ^CR ^CFor F, Cl ,-CH ₃Or CF ₃In some embodiments, R ⁴Be-NHC (=O) OCH (CH ₃)-(cyclopropyl).In some embodiments, R ⁴Be-NHC (=O) OCH (CH ₃)-(phenyl).

In some embodiments, CY is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, through replacing or without substituted pentenyl, through replacing or without substituted cyclohexenyl, or through replacing or without substituted phenyl; Wherein if CY is that then CY is substituted with R through substituted ^CR ^CFor F, Cl ,-CH ₃Or CF ₃In some embodiments, CY is through replacement or without substituted phenyl; Wherein, then should be substituted with R through substituted phenyl if CY is through substituted phenyl ^CR ^CFor F, Cl ,-CH ₃Or CF ₃In some embodiments, CY is a cyclopropyl.In some embodiments, CY is a phenyl.

In some embodiments, CY is through replacement or without substituted phenyl, and wherein if CY is through substituted, then each substituting group on the CY is H or R ^CEach R ^CBe independently selected from H, halogen, C ₁-C ₄Alkyl, C ₁-C ₄Fluoroalkyl, C ₁-C ₄Fluoroalkyloxy, C ₁-C ₄Alkoxyl group and C ₁-C ₄Assorted alkyl.In some embodiments, each R ^CBe independently selected from H, F, Cl ,-CH ₃,-CF ₃,-OCF ₃,-OCH ₃In some embodiments, CY is phenyl, 2-fluorophenyl or 2-chloro-phenyl.In some embodiments, CY is a phenyl.In some embodiments, R ^CFor H, F, Cl ,-CH ₃Or CF ₃

In some embodiments, CY is without replacement or through R ^CThe single replacement.

In some embodiments, R ⁴For

In some embodiments, R ⁴For

In some embodiments, R ⁸For-CH ₃Or-CF ₃In some embodiments, R ⁸For-CH ₃

In some embodiments, R ⁴For

In some embodiments, R ⁴For

In some embodiments, R ⁴For

In some embodiments, R ⁴For

In some embodiments, R ¹⁰Be C ₁-C ₆Alkyl or through replacing or without substituted phenyl.In some embodiments, R ¹⁰Be C ₁-C ₆Alkyl.In some embodiments, R ¹⁰For-CH ₃Or-CH ₂CH ₃In some embodiments, R ¹⁰For the warp replacement or without substituted phenyl.In some embodiments, R ¹⁰Be phenyl.In some embodiments, R ¹⁰Be C ₁-C ₄Alkyl or phenyl.

In some embodiments, each R ^ABe independently selected from F, Cl, Br, I ,-CH ₃,-CF ₃,-OH ,-OCF ₃And-OCH ₃In some embodiments, each RA be independently selected from F, Cl ,-CH ₃,-CF ₃,-OH ,-OCF ₃And-OCH ₃In some embodiments, each R ^ABe independently selected from F, Cl ,-CH ₃,-CF ₃And-OH.In some embodiments, each R ^ABe independently selected from F, Cl ,-CH ₃And-OH.

In some embodiments, each R ^BBe independently selected from F, Cl, Br, I ,-CH ₃,-CF ₃,-OH ,-OCF ₃And-OCH ₃In some embodiments, each RB be independently selected from F, Cl ,-CH ₃,-CF ₃And-OH.In some embodiments, each R ^BBe independently selected from F, Cl ,-CH ₃And-OH.

In some embodiments, each R ^CBe independently selected from F, Cl, Br, I ,-CH ₃,-CF ₃,-OH ,-OCF ₃And-OCH ₃In some embodiments, each R ^CBe independently selected from F, Cl ,-CH ₃,-CF ₃,-OH ,-OCF ₃And-OCH ₃In some embodiments, each R ^CBe independently selected from F, Cl ,-CH ₃,-CF ₃And-OH.In some embodiments, each R ^CBe independently selected from F, Cl ,-CH ₃And-CF ₃In some embodiments, each R ^CBe independently selected from F, Cl and-OH.In some embodiments, each R ^CBe independently selected from F and Cl.

In some embodiments, m is 0 or 1.In some embodiments, m is 0.In some embodiments, m is 1.In some embodiments, p is 0 or 1.In some embodiments, p is 0.In some embodiments, p is 1.

In some embodiments, n is 1,2,3 or 4.In some embodiments, n is 1,2 or 3.In some embodiments, n is 1.In some embodiments, n is 2.In some embodiments, n is 3.In some embodiments, n is 4.

In some embodiments, R ¹For-CO ₂H; M is 0; P is 0, and n is 1; CY is a phenyl.In some embodiments, R ⁸For-CH ₃N is 1; CY is a phenyl.

In some embodiments, described in CY such as table 1 and/or the table 2.

The application contains the arbitrary combination of preceding text to the said group of each variable.In whole specification sheets, select its group and substituting group so that steady component and compound to be provided by those skilled in the art.

In some embodiments, the compound of formula (I) includes but not limited at described in table 1, table 2 and Fig. 1 to 5 those.

Table 1:

# representes indivedual steric isomers; Do not confirm absolute configuration

* mass-spectrometric data

Table 2:

* mass-spectrometric data

Synthesizing of compound

The compound of the synthetic said formula of the application (I) of the combination of use standard synthetic technology or use means known in the art and the said method of the application.In addition, the solvent, temperature and other reaction conditions that provide of the application is variable.

The starting substance that is used for the compound of synthesis type (I) be synthetic or by be purchased the source (such as but be not limited to Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar etc.) obtain.Can through use to introduce as the application provide in each chemical formula the suitable reagent and the condition of discovery different piece revise the general method for preparing compound.

In one aspect, the compound of formula (I) preparation that is described below.

Scheme 1.

In one aspect, the synthetic reaction that starts from Acetacetic acid alkyl ester and methylamine of the compound of formula (I) provides the compound of structure I I.The compound that makes structure I I provides the compound of structure I V with the warp replacement or without substituted 4-halogen-Benzoyl chloride 99min. (structure III) reaction.With the compound of oxyamine and acetic acid treatment structure I V, structure V De is provided isoxazole.Ester group to structure V De isoxazole is hydrolyzed, and the carboxylic acid of structure VI is provided.Curtius takes place in the presence of the oxy-compound of structure VI the carboxylic acid of structure VI resets, and the carbamate compounds of structure VII is provided.

Scheme 2.

In some embodiments, utilize the Suzuki reaction of compound of compound and the structure VIII of structure VII that the compound of structure X is provided.In some embodiments, the Suzuki reaction comprises that use is such as Pd (PPh ₃) ₄Or Pd (dppf) Cl ₂Palladium catalyst.In some embodiments, the Suzuki reaction comprises that use is such as K ₂CO ₃Alkali.The linked reaction of other metal catalytic of the compound of known preparation structure X.

Scheme 3.

In some embodiments, use transition metal-catalyzed reaction conditions to make compound and the boronation reagent react of structure VII, form the boric acid ester compound of structure I X.In some embodiments, the boronation of formation IX is reacted under the existence that is included in suitable alkali (such as potassium acetate) and is used such as Pd (PPh ₃) ₄Or Pd (dppf) Cl ₂Palladium catalyst.Make the boric acid ester compound of structure I X and the compound of structure XII react the compound that forms structure XIII down at the catalytic coupling condition of palladium (Suzuki reaction conditions).

In some embodiments, the compound of formula (I) is as preparing described in the scheme 4.

Scheme 4.

In some embodiments, as in scheme 4, showing, the biphenol compound of structure XIV is prepared as polynuclear compound.The biphenol compound of structure XIV is handled with saturated dihalide based compound (such as glycol dibromide), formed compound cycloalkyl.Cyan-hydrolysis is acid and forms ester by acid, the tricyclic compound of structure XV is provided.In some embodiments, R ^DBe ethyl.In some embodiments, R ^DBe sec.-propyl.Then the tricyclic compound of structure XV is handled in the presence of lewis acidic suitable with Acetyl Chloride 98Min., then ethanoyl is converted into carboxylic acid and carboxylic acid is handled with THIONYL CHLORIDE 97, obtain the chloride of acid of structure XVI.The chloride of acid of utilization structure XVI prepares structure XVII De isoxazole then, as described in the scheme 1.In some embodiments, R is an alkyl.In some embodiments, R is methyl and under hydrolysising condition, R is removed by structure XVII De isoxazole.In some embodiments, R is a benzyl and at hydrogenation conditions (H for example ₂, R is removed by structure XVII De isoxazole under Pd/C).The carboxylic acid of structure XVIII is at oxy-compound CY-CH (R ⁸Carry out Curtius under the existence of)-OH and reset, obtain the carbamate compounds of structure X.

In one aspect, the compound of formula (I) such as in an embodiment elaboration preparation.

Other form of compound

In one aspect, the compound of formula (I) has one or more three-dimensional centers and each three-dimensional center exists with R or S configuration independently.The compound that the application provides comprises all diastereomers and enantiomeric forms.If need, can be through obtaining steric isomer such as and/or the isolating method of steric isomer synthetic through the stereoselectivity of chirality chromatographic column.

Said method of the application and preparation comprise N-oxide compound (suitably time), crystallized form (being also referred to as polymorphic form), the amorphous phase and/or the pharmaceutical salts of the compound that uses the structure with formula (I) and meta-bolites and the active metabolite with active these compounds of same type.In some cases, compound can tautomeric forms exist.All tautomers include in the scope of compound that the application provides.In specific embodiments, the said compound of the application exists with the solvation form with medicinal solvent (such as water, ethanol etc.).In other embodiments, the said compound of the application exists with the non-solvent form.

In some embodiments, be prodrug with the said compound of the application." prodrug " is meant the medicament that can change into parent drug in vivo.In certain embodiments, after the administration, prodrug changes into biology, medicine or the therapeutic activity form of compound with chemical mode in vivo.In certain embodiments, prodrug is metabolized to biology, medicine or the therapeutic activity form of compound with the enzymatic mode through one or more steps or process.

In some embodiments, the site on the aromatic ring of the compound of formula (I) part is easy to carry out various metabolic reactions.On aromatic ring structure, include suitable substituting group in and can reduce, minimize or eliminate this pathways metabolism.In specific embodiments, only for example, can reduce or eliminate aromatic ring is deuterium, halogen or alkyl to the suitable substituting group of the susceptibility of metabolic reaction.

In another embodiment, the said compound of the application carries out mark through isotropic substance or another alternate manner (include but not limited to use chromophore or fluorescence part, bioluminescence marker, or chemiluminescent labeling).

In one aspect, replace, can some treatment advantage be provided because of causing stronger metabolic stability, for example transformation period or reduction dose requirements in the extension body with isotropic substance (such as deuterium).

The application's used " medicinal " is meant biological activity or character and the nontoxic relatively material (such as carrier or thinner) that can not eliminate compound, can with this material can not cause individual administration do not expect biological effect or not with the compsn that contains it in arbitrarily component interact with harmful mode.

In some embodiments, pharmaceutical salts is obtained by the compound and the acid-respons of formula (I).Pharmaceutical salts also can be formed salt and obtained by the compound of formula (I) and alkali reaction.

The said compound of the application can be the formation of pharmaceutical salts form and/or use.The type of said pharmaceutical salts includes but not limited to: (1) acid salt; It by this compound of free alkali form and medicinal mineral acid (for example; Hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid etc.) or with organic acid (for example; Acetate, propionic acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, succsinic acid, oxysuccinic acid, toxilic acid, fumaric acid, trifluoroacetic acid, tartrate, Hydrocerol A, phenylformic acid, styracin, phenylglycollic acid, methylsulfonic acid, ethyl sulfonic acid, 1,2-ethionic acid, 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, toluenesulphonic acids, 2-naphthene sulfonic acid, Whitfield's ointment, Triple Pressed Stearic Acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, Valproic acid etc.) reaction forms; (2) salt that the acid proton that in parent compound, exists forms when metals ion (for example, alkalimetal ion (for example, lithium, sodium, potassium), alkaline earth metal ion (for example, magnesium or calcium), or aluminum ion) is replaced.Under some situations, the said compound of the application can with the organic bases coordination, said organic bases such as but be not limited to thanomin, diethylolamine, trolamine, tromethane, N-methyl glucoside amine, dicyclohexyl amine, three (hydroxymethyl) methylamine.Under other situation, the said compound of the application can with amino acid such as but be not limited to l-arginine, Methionin Methionin etc.) form salt.Be used for and comprise that the acceptable mineral alkali of the compound formation salt of acid proton includes but not limited to white lake, calcium hydroxide, Pottasium Hydroxide, yellow soda ash, sodium hydroxide etc.The sodium salt of the compound of preparation formula in some embodiments, (I).

It should be understood that mentioned pharmaceutical salts comprises its solvent addition form or crystalline form, particularly solvolyte or polymorphic form.Solvolyte contains the solvent of stoichiometry or non-stoichiometric amount, and can in medicinal solvent (such as water, ethanol etc.) crystallisation process, form.When solvent forms hydrate during for water, or when solvent formation alcoholate when be pure.In addition, compound that the application provides can non-solvent form and the existence of solvation form.Generally speaking, the purpose from compound that the application provides and method is regarded as being equal to the non-solvent form with the solvation form.

The said compound of the application (such as the compound of formula (I)) can take various forms, and includes but not limited to amorphous form, pulverize form (milled form) and nanoparticle form.In addition, the said compound of the application comprises crystallized form, is also referred to as polymorphic form.Polymorphic form comprises the different crystal packing arrangement of the compound that identical element is formed.

Some term

Except as otherwise noted, used following term has the given definition of hereinafter otherwise among the application's (comprising specification sheets and claim).It should be noted,, comprise a plurality of indicators otherwise used singulative in the specification sheets and the claim of enclosing " (a, an) " reaches " said " only if context offers some clarification in addition.Except as otherwise noted, otherwise use mass spectrum, NMR, HPLC, protein chemistry, biological chemistry, recombinant DNA technology and pharmacological domestic method.In this application, except as otherwise noted, otherwise use " or " or " with " mean " and/or ".In addition, " comprising (including) " and other form of using a technical term (reaching " included " such as " include ", " includes ") is not for restricted.The used each several part title of the application is only started from organizational goal, and can not be interpreted as the said theme of restriction.

" alkyl " is meant aliphatic hydrocarbon.Alkyl can be saturated or unsaturated alkyl.No matter whether alkyl saturated branched-chain alkyl or the straight chained alkyl of being.Typical case's alkyl comprises but never is limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec.-butyl, the tertiary butyl, amyl group, neo-pentyl, hexyl, allyl group, but-2-ene base, fourth-3-thiazolinyl etc.

" alkoxyl group " is meant (alkyl) O-group, and wherein alkyl is by being defined like the application.

" naphthenic base " is meant cyclopropyl, cyclopropenyl radical, cyclobutyl, cyclobutene base, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl.

Term " halogen " or replacedly " halogen " or " halogenide " mean fluorine, chlorine, bromine or iodine.

Term " fluoroalkyl " is meant that one or more Wasserstoffatomss are by fluorine atom alternate alkyl.

Term " assorted alkyl " is meant that one or more skeletal atoms of alkyl are selected from the alkyl of the atom (for example, oxygen, nitrogen (for example NH or N alkyl), sulphur or its combination) beyond the de-carbon.Aspect of some embodiments, assorted alkyl is meant an alkyl that skeletal atom is an oxygen of alkyl.

Term " optional replace " or " replacements " mean mentioned group instead have one or more individually and be independently selected from halogen ,-CN ,-NH ₂,-OH ,-NH (CH ₃) ,-N (CH ₃) ₂, alkyl, naphthenic base, fluoroalkyl, assorted alkyl, alkoxyl group, Fluoroalkyloxy ,-the S-alkyl or-S (=O) ₂The extra group of alkyl.In some embodiments, optional substituting group be selected from halogen ,-CN ,-NH ₂,-OH ,-NH (CH ₃) ,-N (CH ₃) ₂,-CH ₃,-CH ₂CH ₃,-CF ₃,-OCH ₃And-OCF ₃In some embodiments, be substituted with one or two aforementioned group through substituted radical.In some embodiments, be substituted with in the aforementioned group through substituted radical.

The general health situation that aligns the experimenter who receives treatment " can be accepted " to mean in the used term about preparation, compsn or composition of the application does not have lasting harmful effect.

The used term of the application " adjusting " means direct or indirect and target interacts to change the activity of target, comprises the activity of (only illustrating) intensifier target target activity, the activity that suppresses target, limit target target activity or expansion target.

The used term of the application " regulator " is meant directly or indirectly and the interactional molecule of target.Interaction includes but not limited to the interaction of agonist, partial agonist, inverse agonist and antagonist.In one embodiment, said regulator is an antagonist.

The used term of the application " agonist " is meant the molecule that is bonded to specific receptors and triggers the reaction in the cell, such as compound, medicine, enzyme activator or hormone regulator.Said agonist simulation is bonded to the effect of the endogenic ligand (such as LPA, prostaglandin(PG), hormone or neurotransmitter) of same receptor.

The used term of the application " antagonist " is meant and reduces, suppresses or stop the effect of another molecule or the active molecule of acceptor site, such as compound.Antagonist includes but not limited to competitive antagonist, noncompetitive antaganist, uncontested property antagonist, partial agonist and inverse agonist.

The used term of the application " LPA dependency " is meant the illness or the obstacle that when not having LPA, can not take place or can not take place with same degree.

The used term of the application " LPA mediation " be meant when not having LPA, possibly take place but when LPA exists generable illness or obstacle.

Used term of the application " co-administered " or similar term are intended to contain to the selected therapeutical agent of single patient's administration, and are intended to comprise that wherein said medicament is with identical or different route of administration or at the regimen of identical or different time administration.

The used term of the application " significant quantity " or " treatment significant quantity " are meant to be enough to the medicament of one or more sxs institute's administration to a certain degree of treatment disease or illness or the amount of compound.Any other expectation that the result can be alleviating of disease sign, symptom or the cause of disease and/or alleviation or biosystem changes.For example, for therepic use, " significant quantity " by required make that disease symptoms significantly alleviates clinically comprise the application the amount of disclosure compound compositions.Suitable " effectively " amount in arbitrarily indivedual situations can be used such as the dose escalation study technology and confirm.

The used term of the application " drug regimen " means by mixing or making up more than one activeconstituentss generations and comprise that fixing of activeconstituents reaches the not product of fixed combination.Term " fixed combination " means activeconstituents (for example, the compound of formula (I)) and the two form administration simultaneously patient with single entities or dosage of auxiliary reagent (co-agent).Term " not fixed combination " with activeconstituents (for example means; The compound of formula (I)) and auxiliary reagent as separate entity simultaneously, common or administration patient and do not have concrete restriction pitch time successively, wherein this administration provides two kinds of compounds of significant quantity in patient's body.The latter also is applicable to mixing (cocktail) therapy, for example 3 kinds of administrations or various active composition.

Term " experimenter " or " patient " are contained Mammals.Mammiferous instance includes but not limited to the mankind, chimpanzee, ape, monkey, ox, horse, sheep, goat, pig, rabbit, dog, cat, rodent, rat, mouse, cavy etc.In one embodiment, Mammals is human.

The used term of the application " treatment " (treat; Treating; Treatment) comprise alleviation, weaken or improve disease or illness at least a symptom, prevent extra symptom, suppress disease or illness; For example, preventative and/or therapeutic stops the development, preventative and/or therapeutic palliates a disease or illness, preventative and/or therapeutic make that disease or illness disappear, preventative and/or therapeutic alleviates the illness that caused by disease or illness or preventative and/or therapeutic stops the symptom of disease or illness of disease or illness.

Pharmaceutical composition/preparation and route of administration

In some embodiments, the said compound of the application is mixed with pharmaceutical composition.Use one or more to help active compound is processed into and to become to assign to the compounding pharmaceutical compsn at the medicinal inert of the goods that pharmaceutically use with usual way.Suitable formulations is looked selected route of administration and is decided.The general introduction of the said pharmaceutical composition of the application is referring to (for example) Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.:Mack Publishing Company, 1995); Hoover, John E., Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; With Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams&Wilkins1999), this disclosure content is incorporated among the application with way of reference.

Compound and other chemical composition that the application institute pharmaceutical composition is meant formula (I) are (promptly; The medicinal inert composition) mixture; Said chemical composition such as carrier, vehicle, tackiness agent, weighting agent, suspending agent, seasonings, sweeting agent, disintegrating agent, dispersion agent, tensio-active agent, lubricant, tinting material, thinner, solubilizing agent, wetting agent, softening agent, stablizer, penetration enhancers, wetting agent, skimmer, inhibitor, sanitas, or their one or more combination.Pharmaceutical composition helps compound the organism administration.

The said pharmaceutical prepn of the application can (include but not limited to through a plurality of route of administration in every way; In oral, parenteral (for example, in intravenously, subcutaneous, intramuscular, intramedullary injection, the sheath, directly in the ventricle, intraperitoneal, intralymphatic, nasal injection), the nose, oral cavity, part or percutaneous dosing approach) to individual administration.The said pharmaceutical prepn of the application include but not limited to liquid, aqueous dispersion agent, gala divide powder, solid solution agent, liposome dispersion agent, aerosol, solid dosage, powder agent, immediate release formulation, controlled release preparation, dissolution formulation, tablet, capsule, pill, sustained release preparation, prolongation delivery formulations, pulsed delivery formulations, multiparticulates preparation, and mixed type discharge immediately and controlled release preparation.

In some embodiments, the compound of oral administration formula (I).

In some embodiments, the compound of topical formula (I).In said embodiment; With formula (I) but compound be mixed with various topical drug delivery composition, such as solution, suspensoid, lotion, gelifying agent, paste, shampoo, scrubbing agent, friction agent, smear, medicinal rod, medical bandage, sesame oil, ointment or ointment.In one aspect, with the compound topical of formula (I) to skin.

On the other hand, the compound through inhalation formula (I).

The compound of preparation formula on the other hand, (I) is used for intranasal administration.Said preparation comprises nasal mist, nasal spray etc.

On the other hand, the compound with formula (I) is formulated as eye drops.

Any above-mentioned aspect is following other embodiment, wherein with the compound of the formula (I) of significant quantity: (a) through whole body administration Mammals; And/or (b) oral administration Mammals; And/or (c) intravenous administration Mammals; And/or (d) through the inhalation Mammals; And/or (e) come the administration Mammals through intranasal administration; Or and/or (f) through the drug administration by injection Mammals; And/or (g) topical Mammals; And/or (h) come administration through dosing eyes; And/or (i) per rectum administration Mammals; And/or (j) non-whole body or topical Mammals.

Any above-mentioned aspect comprises other embodiment of the single administration of effective quantification compound, comprises other embodiment, and wherein (i) is with the compound single administration; (ii) in one day to Mammals multiple dosing compound; (iii) uninterrupted administration; Or (iv) successive administration.

Any above-mentioned aspect comprises other embodiment of the compound of multiple dosing significant quantity, comprises other embodiment, wherein: (i) give drug compound continuously or off and on: with the single dose form administration; (ii) the time between the multiple dosing is per 6 hours; Gave drug compound to Mammals in (iii) per 8 hours; Gave drug compound to Mammals in (iv) per 12 hours; Gave drug compound to Mammals in (iv) per 24 hours.In other or alternate embodiment, said method comprises the off-drug period, wherein temporary transient interruption of the administration compound or the temporary transient dosage that reduces the drug compound of giving; , restarts when finishing the off-drug period to drug compound.In one embodiment, the length of off-drug period is not wait to 1 year by 2 days.

In certain embodiments, with the part but not the said compound of systemic fashion administration the application.

In some embodiments, the said compound of topical the application.In some embodiments, the said compound of whole body administration the application.

In some embodiments, pharmaceutical prepn is tablet form.In other embodiments, the pharmaceutical prepn of the compound of formula (I) is Capsule form.

In one aspect, the liquid preparation formulation of oral administration is and is selected from following aqueous suspensions or solution form: it includes but not limited to moisture oral dispersant, emulsion, solution, elixir, gelifying agent and syrup.

For for the administration that sucks, the compound of formula (I) is formulated as aerosol, mist agent or powder agent form to use.

For trans-oral or sublingual administration, compsn can be taked tablet, the lozenge prepared in a usual manner or gelifying agent form.

In some embodiments, the compound with formula (I) is through the skin formulation.

In one aspect, the compound of formula (I) is mixed with the pharmaceutical composition that is suitable for intramuscular, subcutaneous or intravenous injection.

In some embodiments, but but the said compound topical of the application and can be mixed with various topical drug delivery composition, such as solution, suspensoid, lotion, gelifying agent, paste, medicinal rod, sesame oil, ointment or ointment.

In some embodiments, the compound with formula (I) is formulated as in the rectal compositions (such as enema, rectal gel agent, rectum foaming agent, rectum aerosol, suppository, jelly suppository or enema,retention).

Medication and regimen

In one embodiment, the compound of formula (I) is used to prepare and is used to treat LPA dependency or the disease of LPA mediation or the medicine of illness.In addition; Be used to treat the experimenter's who needs this treatment the said any disease of the application or the method for illness and comprise the pharmaceutical composition to this experimenter's drug treatment significant quantity, it comprises compound or pharmaceutically acceptable salt thereof, active metabolite, prodrug or the solvolyte of at least a formula (I).

In certain embodiments, administration contains the said compound compositions of the application to be used for preventative and/or therapeutic treatment.In some therapeutic is used, be enough to cure or at least part stop disease or illness the amount of at least a symptom to the said compsn of patient's administration of suffering from this disease or illness.For this purposes effectively amount by the severity of disease or illness and the course of disease, previous therapy, patient's healthy state, body weight and to the reaction of medicine, and treatment doctor's judgement decide.The optional definite treatment of method significant quantity through including but not limited to the dosage escalation clinical trial.

In prophylactic application, will contain the said compound compositions of the application to easy infection specified disease, obstacle or illness or patient's administration with specified disease, obstacle or illness risk.

In certain embodiments, can or temporarily suspend specified time length (that is, " off-drug period ") with the temporary transient reduction of the dosage of institute's administration medicine.

The used dosage of adult treatment usually in 0.01mg-5000mg/ days scopes or about 1mg to about 1000mg/ days.In one embodiment, with single dose or separate doses desired amount is provided easily.

The patient selects

Aspect disease that relates to prevention or treatment LPA mediation or illness any above-mentioned, comprise other embodiment of identifying the patient through screening LPA acceptor gene SNP.But the patient is further selected in the increase of LPA expression of receptor in the based target tissue.Method through including but not limited to RNA blotting (northern blotting), Western blotting (western blotting), quantitative PCR (qPCR), flow cytometry, radioautography (using small molecules radioligand or PET part) is measured the LPA expression of receptor.In some embodiments, based on through the serum of mass-spectrometer measurement or organize LPA concentration to select the patient.In some embodiments, select the patient based on combination (the LPA concentration of increase and the LPA expression of receptor of increase) with marked.

Combined therapy

Under some situation, aptly the compound of at least a formula (I) and other therapeutical agent are made up administration.

In a specific embodiments; The compound of co-administered formula (I) and second therapeutical agent; The compound of its Chinese style (I) and second therapeutical agent are regulated the different aspect of the disease of treating, obstacle or illness, than individually dosed therapeutical agent bigger comprehensive benefit are provided thus.

For the said combination treatment of the application, the dosage of co-administered compound look the type of used common medicine, used concrete medicine, the disease of treating or illness etc. and change to some extent.In other embodiments, when with one or more other therapeutical agent co-administereds, the compound that the application is provided and one or more other therapeutical agents are simultaneously or administration successively.

If administration simultaneously, then with (only for example) single, Unified Form, or various ways provides multiple therapeutical agent.

In said another embodiment of the application, treatment comprises that the method for the proliferative disorders of cancer comprises compound and one or more carcinostatic agents and/or the radiotherapeutic combination of administration Mammals formula (I).

In one aspect, the compounds for treating of formula (I) or alleviate mammiferous fibrosis.In one aspect, compound and one or more immunosuppressor with formula (I) makes up administration.In some embodiments, the compound and the cortin of Medicine-feeding type (I).

In described another embodiment of the application; The illness of treatment LPA dependency or LPA mediation or the method for disease (such as the therapy of breathing illness (for example, pulmonary fibrosis, asthma, COPD, rhinitis)) comprise the said compound of administration patient the application, pharmaceutical composition or medicine and at least a combination that is used to treat the medicament of breathing illness.

In some embodiments, to the compound of patient's Medicine-feeding type (I) and the combination of antiphlogiston.

In one embodiment, to the compound of patient's Medicine-feeding type (I) and the combination that can suck cortin.

Embodiment

Only illustration purpose provides these embodiment and does not limit the scope of claim that the application provides presented for purpose of illustration.

Synthesizing of compound

(R)-2 '-the chloro-α-Jia Jibianchun

Use people's such as Meier method (Tetrahedron, 1996,52,589; Method 3) reductase 12 '-chloro-acetophenone (Aldrich), obtain (R)-2 '-the chloro-α-Jia Jibianchun.(use Chiralcel OD to utilize 99: 1 hexanes: the HPLC of ethanol elution through acetic ester derivative (making through benzylalcohol and Acetyl Chloride 98Min. and triethylamine are reacted in methylene dichloride) analyzes and measures %e.e..R isomer RT is 4.3 minutes).

(S)-2 '-the chloro-α-Jia Jibianchun

Use people's such as Meier method (Tetrahedron, 1996,52,589; Method 3) reductase 12 '-chloro-acetophenone (Aldrich), obtain (S)-2 '-the chloro-α-Jia Jibianchun.(use Chiralcel OD to utilize 99: 1 hexanes: the HPLC of ethanol elution through acetic ester derivative (making through benzylalcohol and Acetyl Chloride 98Min. and triethylamine are reacted in methylene dichloride) analyzes and measures %e.e..S isomer RT is 5.3 minutes).

(R)-2 '-the fluoro-α-Jia Jibianchun

Use people's such as Meier method (Tetrahedron, 1996,52,589; Method 3) reductase 12 '-fluoro acetophenone (Aldrich), obtain (R)-2 '-the fluoro-α-Jia Jibianchun.(use Chiralcel OD to utilize 99.8: 0.2 hexanes: the HPLC of ethanol elution through acetic ester derivative (making through benzylalcohol and Acetyl Chloride 98Min. and triethylamine are reacted in methylene dichloride) analyzes and measures %e.e..R isomer RT is 5.9 minutes).

(S)-2 '-the fluoro-α-Jia Jibianchun

Use people's such as Meier method (Tetrahedron, 1996,52,589; Method 3) reductase 12 '-fluoro acetophenone (Aldrich), obtain (S)-2 '-the fluoro-α-Jia Jibianchun.(use Chiralcel OD to utilize 99.8: 0.2 hexanes: the HPLC of ethanol elution through acetic ester derivative (making through benzylalcohol and Acetyl Chloride 98Min. and triethylamine are reacted in methylene dichloride) analyzes and measures %e.e..S isomer RT is 6.7 minutes).

Embodiment 1:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of cyclopropane-carboxylic acid (compound 1)

Step 1:3-methylamino-but-2-ene acid methyl esters: room temperature to methyl acetoacetate (29.4g, (33wt% is in EtOH 253mmol) dropwise to add methylamine in the solution in MeOH (30mL); 48mL, 385mmol).Reaction mixture was stirred 1 hour, concentrate then and dry, the title compound of the crystalline solid forms that obtains being white in color.

Step 2:2-(4-bromo-benzoyl-)-3-oxo-methyl-butyrate: to the 3-methylamino-(5.0g 39.1mmol) adds pyridine (3.7mL) in the solution in THF (70mL) to but-2-ene acid methyl esters.Mixture is cooled to 0 ℃, and lasts 2 minutes and dropwise add 4-bromo-benzoyl chloride (8.55g, 39.1mmol) solution in THF (30mL).Last 1 hour reaction mixture is heated to room temperature then in stirred overnight at room temperature.Implement the water-based aftertreatment, obtain title compound.

Step 3:5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-methyl-formiate: make 2-(4-bromo-benzoyl-)-3-oxo-methyl-butyrate (11g; 39mmol) with hydroxy amine hydrochloric acid salt (2.66g; 39mmol) in acetate (50mL), mix, and reaction mixture was stirred 1 hour at 115 ℃.After the cooling, implement the water-based aftertreatment, obtain title compound.

Step 4:5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid: (2g, (7g is 23.6mmol) in MeOH (50mL) and H 47.7mmol) to be added to 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-methyl-formiate with Lithium Hydroxide MonoHydrate ₂In the solution among the O (10mL), and reaction mixture stirred 1 hour at 60 ℃.Implement acid aftertreatment, obtain title compound.

Step 5: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-phenyl-ethyl ester: with 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid (2.0g; 7.09mmol) and triethylamine (0.99mL, 7.09mmol) dissolving in toluene (50mL).(1.5mL 7.09mmol), adds (R)-(+)-1-phenylethyl alcohol (0.865g, 7.09mmol subsequently to add diphenyl phosphoryl azide; Be available commercially or that the application of poetic atmosphere method said or in following document prepares: E.J.Corey et al.J.Am.Chem.1987 for example, 109,5551-5553), and reaction mixture stirred 4 hours at 80 ℃.Enriched mixture, and come the purifying residue through silica gel chromatography, obtain title compound.

Step 6:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid: make [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-phenyl-ethyl ester (0.248g; 0.62mmol), 4-(1 '-carboxyl-cyclopropyl) phenyl-boron dihydroxide (0.160g; 0.62mmol) and yellow soda ash (0.155g is 1.85mmol) 2: 1DME: H ₂Mix among the O.With solution with nitrogen purge 10 minutes, add then two (triphenylphosphine) palladium chloride (II) (0.047g, 0.06mmol).With reaction mixture extra 10 minutes, in ST, stirred 2 hours then at 80 ℃ with nitrogen purge.Mixture is allocated in EtOAc and H ₂Between the O, and use the EtOAc aqueous layer extracted.With the organic layer that merges through MgSO ₄Drying is filtered and is concentrated, and comes the purifying residue through silica gel chromatography, obtains title compound.

Embodiment 1a:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-bases]-biphenyl-4-yl }-substituting of cyclopropane-carboxylic acid (compound 1) synthesize

Step 1:1-(biphenyl-4-yl) Trimetylene formonitrile HCN: ((161.6g is 2890mmol) in the solution in water (170mL) and toluene (550mL) 289mmol) to be added to KOH for VWR scientific, 55.7g with 4-phenyl-phenylacetonitrile in room temperature.(9.2g, 29mmol), (64.9g 347mmol), and is heated to 65 ℃ with solution and spends the night to add glycol dibromide subsequently to add Tetrabutyl amonium bromide.Show the reaction completion through TLC (10%EtOAc/ hexane).Organic layer is used the Hydrogen chloride extracted twice, and dry and evaporation obtains 63g1-(biphenyl-4-yl) Trimetylene formonitrile HCN.

Step 2:1-(biphenyl-4-yl) cyclopropane-carboxylic acid: with 1-(biphenyl-4-yl) Trimetylene formonitrile HCN (63g, 288mmol), KOH (1130mmol) and terepthaloyl moietie (350mL) is heated to 160 ℃ and keep 6 hours (showing that through LCMS reaction accomplishes).Solution is cooled to room temperature, adds entry (1.5L) and, be settled out product the solution acidifying.Product is upward spent the night at big Buchner (product forms the gel like suspension).The wet solid of gained is used CH ₂Cl ₂(～2L) and water extraction, dry and evaporation obtains～60g 1-(biphenyl-4-yl) cyclopropane-carboxylic acid, and its as original uses in next step.

Step 3:1-(biphenyl-4-yl) cyclopropane carboxylic acid acetoacetic ester: with 1-(biphenyl-4-yl) cyclopropane-carboxylic acid (10g, 42mmol), ethanol (100mL) and sulfuric acid (40mL) is heated to 65 ℃ and kept 4 hours.Product is used CH ₂Cl ₂And water (2X) extraction, dry and evaporation obtains 9.5g 1-(biphenyl-4-yl) cyclopropane carboxylic acid acetoacetic ester.

Step 4:1-(4 '-acetyl biphenyl-4-yl) the cyclopropane carboxylic acid acetoacetic ester: (9g is 33.8mmol) at CH to 1-(biphenyl-4-yl) cyclopropane carboxylic acid acetoacetic ester ₂Cl ₂Add in the solution (100mL) aluminum chloride (9.4g, 71mmol), add subsequently Acetyl Chloride 98Min. (5.5g, 71mmol).Solution stirring at room 1.5 hours, is slowly poured in the water then.Separate organic layer and water extraction 2 times.Dry and evaporation obtains the 11.3g title compound with organic layer.

Step 5:4 '-(1-(ethoxy carbonyl) cyclopropyl) biphenyl-4-carboxylic acid: at～10 ℃ to 1-(4 '-acetyl biphenyl-4-yl) cyclopropane carboxylic acid acetoacetic ester (10.1g; 33mmol) add bromine (26.4g in the solution in the Zai diox (200mL); 165mmol), sodium hydroxide (22.4g, 561mmol) solution in water (150mL).Solution stirring at room 30 minutes, is poured in the water (500mL) and used the Hydrogen chloride acidifying.Adding Sodium Pyrosulfite dissipates up to brown bromine look.With the product filtration and 40 ℃ of drying under vacuum overnight, obtain 10g4 '-(1-(ethoxy carbonyl) cyclopropyl) biphenyl-4-carboxylic acid.

Step 6:3-methylamino-but-2-ene acid benzyl ester: to benzyl acetoacetate (29g, 151mmol) add in the solution in ethanol (30mL) methylamine (33%, in ethanol, 7.02g, 226mmol).With solution stirring at room 2 hours, evaporation subsequently, obtain yellow oil (～30g).

Step 7:1-(4 '-(2-(benzyl oxygen base carbonyl)-3-(methylamino) but-2-ene acyl group) biphenyl-4-yl) cyclopropane carboxylic acid acetoacetic ester: with 4 '-(1-(ethoxy carbonyl) cyclopropyl) biphenyl-4-carboxylic acid (4.47g; 14.4mmol), (2.3mL 32mmol) is heated to 80 ℃ and kept 1 hour for ethylene dichloride (50mL), DMF (0.1mL), THIONYL CHLORIDE 97.(forming) through a small amount of aliquot (100 μ L) being added in the solution of benzylamine in acetonitrile and monitoring chloride of acid through lcms analysis benzyl acid amides.Solution is evaporated on rotatory evaporator and adds THF (10mL).With the solution of chloride of acid in THF through syringe be added to 3-methylamino-but-2-ene acid benzyl ester (3.23g, 15.8mmol) and pyridine (2.4mL is 30.2mmol) in the solution in THF (50mL).Solution was stirred 2 hours at 50 ℃, then volatile matter is used the rotatory evaporator evaporation, obtain crude product.

Step 8:5-(4 '-(1-(ethoxy carbonyl) cyclopropyl) biphenyl-4-yl)-3-methyl-isoxazole-4-benzyl carboxylate: add in the thick material that in by the front reaction, obtains hydroxy amine hydrochloric acid salt (1.5g, 21.6mmol) and acetate (50mL).Solution is heated to 95 ℃ and kept 30 minutes, is cooled to room temperature, use CH ₂Cl ₂With water extraction (4 times, for the second time with alkalize with sodium hydrogencarbonate for the third time).Drying, the evaporation and on post purifying (0 to 20%EtOAc/ hexane), obtain the 3.3g product.

Step 9:5-(4 '-(1-(ethoxy carbonyl) cyclopropyl) biphenyl-4-yl)-3-methyl-isoxazole-4-carboxylic acid: (1g, 2.1mmol) solution in ETHYLE ACETATE (10mL) outgased 10 minutes with nitrogen the benzyl ester that will be obtained by step 8.(0.2g 0.2mmol) and with solution uses the hydrogen bubbling through air bag to add 10% palladium/gac.The hydrogen capsule is remained on the headspace and with solution stirring 1.5 hours.Reaction mixture with ethanol and acetone diluted (lysate), through diatomite filtration and evaporation, is obtained the 700mg product.

Step 10:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-base]-biphenyl-4-yl }-the cyclopropane carboxylic acid acetoacetic ester: to the acid (0.5g that obtains by step 9; 1.28mmol) add (R)-1-phenylethyl alcohol (0.16g in the solution in toluene (5mL); 1.34mmol), triethylamine (0.26g; 2.56mmol) and diphenyl phosphoryl azide (0.39g, 1.4mmol).Solution is heated to 80 ℃ and kept 1 hour, is cooled to room temperature and water extraction 3 times.Dry and evaporation obtains the 0.61g product with organic layer.Product further through column chromatography purifying (0 to 40%EtOAc/ hexane), is obtained 0.42g pure products (65%), and it is an oily matter, is foam when vacuum-drying.

Step 11:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid: to ethyl ester (22.7g; 44mmol) add in the solution in methyl alcohol (300mL) Lithium Hydroxide MonoHydrate (9.1g, 222mmol).Solution is heated to 65 ℃ and kept 2 hours, extraction and wash in methylene dichloride with Hydrogen chloride.Dry and the evaporation with organic layer obtains 20.8 gram products.

Embodiment 1b:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-bases]-biphenyl-4-yl }-substituting of cyclopropane-carboxylic acid (compound 1) synthesize

Step 1:1-(biphenyl-4-yl) cyclopropane carboxylic acid isopropyl propionate: with 1-(biphenyl-4-yl) cyclopropane-carboxylic acid (10g, 42mmol), (6.8mL 92mmol) is heated to 65 ℃ and kept 4 hours for Virahol (100mL), THIONYL CHLORIDE 97.Add sulfuric acid (20mL) and 65 ℃ of heated overnight.Product is used CH ₂Cl ₂With water extraction (2X), dry and evaporation obtains the 10.8g title compound.

Step 2:1-(4 '-acetyl biphenyl-4-yl) the cyclopropane carboxylic acid isopropyl propionate: (10.2g is 36mmol) at CH to 1-(biphenyl-4-yl) cyclopropane carboxylic acid isopropyl propionate ₂Cl ₂Add in the solution (100mL) aluminum chloride (10.2g, 76.5mmol), add subsequently Acetyl Chloride 98Min. (5.97g, 76.5mmol).Solution stirring at room 1.5 hours, is slowly poured in the water then.Separate organic layer also with sodium tartrate potassium solution (solution of 20g in 250mL water) extraction 1 time.Dry and evaporation obtains the 12.6g title compound with organic layer.

Step 3:4 '-(1-(isopropoxy carbonyl) cyclopropyl) biphenyl-4-carboxylic acid: at～10 ℃ to 1-(4 '-acetyl biphenyl-4-yl) cyclopropane carboxylic acid isopropyl propionate (11.6g; 36mmol) add bromine (28.8g in the solution in the Zai diox (200mL); 180mmol), sodium hydroxide (24.5g, 612mmol) solution in water (150mL).Solution stirring at room 30 minutes, is poured in the water (500mL) and used the Hydrogen chloride acidifying.Adding Sodium Pyrosulfite dissipates up to brown bromine look.Product is filtered, and, obtain the 10g title compound 40 ℃ of drying under vacuum overnight.

Step 4:1-(4 '-(2-(benzyl oxygen base carbonyl)-3-(methylamino) but-2-ene acyl group) biphenyl-4-yl) cyclopropane carboxylic acid isopropyl propionate: with 4 '-(1-(isopropoxy carbonyl) cyclopropyl) biphenyl-4-carboxylic acid (9.2g; 28mmol), (5.5mL 62mmol) is heated to 75 ℃ and kept 1.5 hours for ethylene dichloride (50mL), DMF (0.1mL), THIONYL CHLORIDE 97.(form through a small amount of aliquot (100 μ L) being added in the solution of benzylamine in acetonitrile and monitoring chloride of acid through lcms analysis benzyl acid amides; Do not observe starting substance through LCMS).Solution is evaporated on rotatory evaporator and adds THF (10mL).With the solution of chloride of acid in THF through syringe be added to 3-methylamino-but-2-ene acid methyl esters (4.0g, 31.2mmol) and pyridine (5.5mL is 70mmol) in the solution in THF (50mL).With solution in stirred overnight at room temperature.Volatile matter is evaporated on rotatory evaporator, obtain crude product.

Step 5:5-(4 '-(1-(isopropoxy carbonyl) cyclopropyl) biphenyl-4-yl)-3-methyl-isoxazole-4-carboxylate methyl ester: in the starting substance that obtains by the front reaction, add hydroxy amine hydrochloric acid salt (2.9g, 42mmol) and acetate (50mL).Solution is heated to 100 ℃ and kept 30 minutes, is cooled to room temperature, use CH ₂Cl ₂With water extraction (4 times, for the second time with alkalize with sodium hydrogencarbonate for the third time).Organic phase is dry, evaporation and purifying (220g silica gel on post; 0 to 20%EtOAc/ hexane), obtain the 6g product.

Step 6:5-(4 '-(1-(propoxycarbonyl) cyclopropyl) biphenyl-4-yl)-3-methyl-isoxazole-4-carboxylic acid: to the methyl esters (5.2g that obtains by step 5; 12.4mmol) add sodium hydroxide (1.5g, 37.2mmol) solution in water (40mL) in the solution in THF (100mL) and ethanol (20mL).With solution stirring at room 3 hours.General～50mL solvent evaporation also adds 200mL water.Product is separated out by solution precipitation with Hydrogen chloride, obtain pH 2.Product is separated through filtering, obtain 4.6 gram title compounds.

Step 7:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-base]-biphenyl-4-yl }-the cyclopropane carboxylic acid isopropyl propionate: to the acid (4.0g that obtains by step 6; 10mmol) add R-1-phenylethyl alcohol (1.33g in the solution in toluene (50mL); 11mmol), triethylamine (2.02g; 20mmol) and diphenyl phosphoryl azide (3.16g, 11.5mmol).Solution is heated to 80 ℃ and kept 1 hour, is cooled to room temperature and water extraction 3 times.Dry and evaporation obtains the 5.7g title compound with organic layer.

Step 8:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid: to the isopropyl ester (5.2g that obtains by step 7; 10mmol) add NaOH (2g, 50mmol) solution in water (10mL) in the solution in THF (30mL), MeOH (10mL).Solution is heated to 65 ℃ and kept 5 hours.Solution is cooled to room temperature, with methylene dichloride and Hydrogen chloride extraction.With organic phase dry and evaporation and with product through column chromatography purifying (0 to 60%EtOAc/ hexane), obtain～3.5 gram products.

Embodiment 2:1-{4 '-[3-methyl-4-((R)-1-neighbour-tolyl-ethoxy carbonyl amino)-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of cyclopropane-carboxylic acid (compound 3)

Step 1:1-(4-bromo-phenyl)-Trimetylene formonitrile HCN: (14.3g is 255mmol) at H with Pottasium Hydroxide ₂Dissolving in O (5mL) and the toluene (40mL).Add 4-bromophenyl acetonitrile (5.0g, 25.5mmol) and Tetrabutyl amonium bromide (0.41g, 1.3mmol), last 10 minutes subsequently and dropwise add glycol dibromide (3.25mL, 38mmol).Reaction mixture is implemented aftertreatment in 2 hours then in stirring at room, obtain title compound.

Step 2:1-(4-bromo-phenyl)-cyclopropane-carboxylic acid: make 1-(4-bromo-phenyl)-Trimetylene formonitrile HCN (5g, 22.5mmol) and Pottasium Hydroxide (5g 89.3mmol) mixes in terepthaloyl moietie (70mL), and reaction mixture was stirred 4 hours at 180 ℃.Pour mixture into H ₂Among the O, acidifying is also filtered, and obtains title compound.

Step 3:1-(4-bromo-phenyl)-cyclopropane carboxylic acid acetoacetic ester: (5g, 20.7mmol) solution in EtOH (50mL) is handled with sulfuric acid (2mL), and reaction mixture was stirred 1 hour at 75 ℃ with 1-(4-bromo-phenyl)-cyclopropane-carboxylic acid.Mixture is implemented aftertreatment, obtain title compound.

[4-(4,4,5 for step 4:1-; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester: make 1-(4-bromo-phenyl)-cyclopropane carboxylic acid acetoacetic ester (3.6g; 13.4mmol), join boric acid two pinacol ester (3.37g; 16.1mmol) and potassium acetate (2.8g, 29mmol) 1, mixing in the 4-diox (30mL).With nitrogen purge solution 10 minutes, (0.50g 0.65mmol) and with reaction mixture was heated to 80 ℃ and kept 2 hours to add (1,1 '-two (diphenylphosphino) ferrocene)-palladium chloride (II) then.Implement the water-based aftertreatment, carry out silica gel chromatography (among the 0-30%EtOAc in hexane) subsequently, obtain title compound.

Step 5: (R)-1-neighbour-tolyl-ethanol: with (S)-(-)-2-methyl-CBS-oxazole borine (3.72g, 13.4mmol) dissolving in THF (60mL).(2M is in THF to add borine methyl thioether complex compound; 36.6mL, 73.3mmol), and mixture is cooled to 0 ℃.Last 1 hour and add 2 '-(15g, the 111mmol) solution in THF (30mL) are implemented aftertreatment to mixture to methyl acetophenone then, obtain having the liquid of white precipitate.Add hexane, and filter suspension and remove deposition, and concentrated gained filtrating, obtain the title compound of 93%e.e.

Step 6: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-neighbour-tolyl-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and (R)-1-neighbour-tolyl-ethanol to prepare according to the method described in embodiment 1 step 5.

Step 7:1-{4 '-[3-methyl-4-((R)-1-neighbour-tolyl-ethoxy carbonyl amino)-isoxazole-5-base]-biphenyl-4-yl }-the cyclopropane carboxylic acid acetoacetic ester: according to the use of the method described in embodiment 1 step 6 [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine (R)-1-neighbour-tolyl-ethyl ester, [4-(4 for 1-; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-cyclopropane carboxylic acid acetoacetic ester and tetrakis triphenylphosphine palladium (0) prepare.

Step 8:1-{4 '-[3-methyl-4-((R)-1-neighbour-tolyl-ethoxy carbonyl amino)-isoxazole-5-base]-biphenyl-4-yl }-cyclopropane-carboxylic acid: to 1-{4 '-[3-methyl-4-((R)-1-neighbour-tolyl-ethoxy carbonyl amino)-isoxazole-5-base]-biphenyl-4-yl }-cyclopropane carboxylic acid acetoacetic ester (0.36mmol) is 2: 1MeOH: H ₂Add Lithium Hydroxide MonoHydrate (1.1mmol) in the solution among the O, and with reaction mixture in stirring at room until observing no starting substance through analytical LCMS.Mixture is extracted with 1N HCl acidified aqueous solution and with EtOAc.The organic layer that merges is dry, filtration and concentrated obtain title compound.

Embodiment 3a: (R)-1-{4 '-[4-(1-cyclopropyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of cyclopropane-carboxylic acid (compound 6)

Step 1: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine 1-cyclopropyl-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and Alpha-Methyl Trimetylene methyl alcohol to prepare according to the method described in embodiment 1 step 5.

Step 2:1-{4 '-[4-(1-cyclopropyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-base]-biphenyl-4-yl }-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine 1-cyclopropyl-ethyl ester and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares; Use Chiracel OD post (97: 3 hexanes: EtOH) come the isolated material of purifying, enantiomer A and enantiomer B are provided then through preparation property HPLC.Enantiomer A RT is 27 minutes, and enantiomer B RT is 33 minutes.

Step 3: (R)-1-{4 '-[4-(1-cyclopropyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-base]-biphenyl-4-yl-cyclopropane-carboxylic acid: according to the method described in embodiment 2 steps 8 use from embodiment 3a step 2 (1-{4 '-[4-(1-cyclopropyl-ethoxy carbonyl amino)-3-methyl-isoxazole-5-base]-biphenyl-4-yl-the cyclopropane carboxylic acid acetoacetic ester) enantiomer B prepare.

Embodiment 3b: (R)-1-{4 '-[4-(1-cyclopropyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-bases]-biphenyl-4-yl }-substituting of cyclopropane-carboxylic acid (compound 6) synthesize

Step 1: (R)-Alpha-Methyl Trimetylene methyl alcohol: method (Tetrahedron, 1996,52,589 of using people such as similar Meier; Method 3) reduction Cyclopropyl Methyl Ketone (Aldrich), obtain (R)-Alpha-Methyl Trimetylene methyl alcohol.

Step 2:1-(R)-[5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine 1-cyclopropyl-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and (R)-Alpha-Methyl Trimetylene methyl alcohol to prepare according to the method described in embodiment 1 step 5.

Step 3: (R)-1-{4 '-[4-(1-cyclopropyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-base]-biphenyl-4-yl }-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use 1-(R)-[5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine 1-cyclopropyl-ethyl ester and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares; Excessive through the enantiomerism of the definite material of isolating of chirality HPLC is 92% (Chiracel OD post (less important isomer RT is 27 minutes for 97: 3 hexanes: EtOH, 1ml/min, and main isomer RT is 32 minutes).

Step 4: (R)-1-{4 '-[4-(1-cyclopropyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-base]-biphenyl-4-yl-cyclopropane-carboxylic acid: according to the method described in embodiment 2 steps 8 use (R)-(1-{4 '-[4-(1-cyclopropyl-ethoxy carbonyl amino)-3-methyl-isoxazole-5-base]-biphenyl-4-yl-the cyclopropane carboxylic acid acetoacetic ester) prepare.

Synthesizing of embodiment 4:1-(4 '-{ 4-[(R)-1-(2-chloro-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 8)

Step 1: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-(2-chloro-phenyl)-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and (R)-1-(2-chloro-phenyl)-ethanol to prepare according to the method described in embodiment 1 step 5.

Step 2:1-(4 '-{ 4-[(R)-1-(2-chloro-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid: prepare according to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-(2-chloro-the phenyl)-ethyl ester of the method described in embodiment 1 step 6 and 4-(1 '-carboxyl-cyclopropyl) phenyl-boron dihydroxide.

Synthesizing of embodiment 5:1-(4 '-{ 3-methyl-4-[(R)-1-(2-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 9)

Step 1: (R)-1-(2-trifluoromethyl-phenyl)-ethanol: according to the method described in embodiment 2 steps 5 use 2 '-(trifluoromethyl) methyl phenyl ketone prepares.

Step 2: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-(2-trifluoromethyl-phenyl)-ethyl ester: use (R)-1-(2-trifluoromethyl-phenyl)-ethanol and 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid to prepare according to the method described in embodiment 1 step 5; Use Chiracel OD post (98.6: 1.4 hexanes: EtOH) come the isolated material of purifying, obtain title compound through preparation property HPLC.

Step 3:1-(4 '-3-methyl-4-[(R)-1-(2-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-base }-biphenyl-4-yl)-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine (R)-1-(2-trifluoromethyl-phenyl)-ethyl ester and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 4:1-(4 '-{ 3-methyl-4-[(R)-1-(2-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: use 1-(4 '-{ 3-methyl-4-[(R)-1-(2-trifluoromethyl-phenyl)-ethoxy carbonyl amino]-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 2 steps 8.

Embodiment 6:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of Cyclopentane carboxylic acid (compound 11)

Step 1:1-(4-bromo-phenyl)-Cyclopentane carboxylic acid ethyl ester: 0 ℃ to 4-bromophenyl ETHYLE ACETATE (2g, 8.2mmol) add in the solution in DMF (20mL) sodium hydride (60%, in MO; 0.72g, 18.1mmol), and with mixture stirring 10 minutes.Add 1, the 4-dibromobutane (1.07mL, 9.0mmol), and with reaction mixture stirring at room 30 minutes.In case observe no starting substance through analytical TLC, with EtOAc and 10%HCl aqueous solution aftertreatment mixture, and come the thick material of purifying through silica gel chromatography, obtain title compound.

[4-(4 for step 2:1-; 4,5,5-tetramethyl--[1; 3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the Cyclopentane carboxylic acid ethyl ester: use 1-(4-bromo-phenyl)-Cyclopentane carboxylic acid ethyl ester and couplet boric acid two pinacol esters to prepare according to the method described in embodiment 2 steps 4.

Step 3:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-bases]-biphenyl-4-yl }-the Cyclopentane carboxylic acid ethyl ester: make [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-phenyl-ethyl ester (0.077g, 0.19mmol), [4-(4,4 for 1-; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-Cyclopentane carboxylic acid ethyl ester (0.079g; 0.23mmol) and salt of wormwood (0.066g is 0.48mmol) 2: 1DME: H ₂Mix among the O (3mL).With solution with nitrogen purge 5 minutes, add then tetrakis triphenylphosphine palladium (0) (0.022g, 0.02mmol).With mixture extra 5 minutes, reaction mixture was stirred 1.5 hours in ST at 90 ℃ then with nitrogen purge.Implement the water-based aftertreatment, carry out silica gel chromatography subsequently, title compound is provided.

Step 4:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-Cyclopentane carboxylic acid: with 1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-Cyclopentane carboxylic acid ethyl ester (0.060g; 0.11mmol) 1; Solution in the 4-diox (2mL) is handled with the 1N LiOH aqueous solution (1mL), and with reaction mixture 60 ℃ of stirred overnight.Implement acid aftertreatment, carry out silica gel chromatography (among the 0-50%EtOAc in hexane) subsequently, obtain title compound.

Embodiment 7:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of NSC 4535 (compound 10)

Step 1:1-(4-bromo-phenyl)-cyclobutane carboxylate: use 4-bromophenyl ETHYLE ACETATE and 1 according to the method described in embodiment 6 steps 1, the 3-dibromopropane prepares.

[4-(4 for step 2:1-; 4,5,5-tetramethyl--[1; 3,2] dioxo bora pentamethylene-2-yl)-phenyl]-cyclobutane carboxylate: use 1-(4-bromo-phenyl)-cyclobutane carboxylate and couplet boric acid two pinacol esters to prepare according to the method described in embodiment 2 steps 4.

Step 3:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclobutane carboxylate: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-phenyl-ethyl ester and 1-according to the method described in embodiment 6 steps 3; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-cyclobutane carboxylate prepares.

Step 4:1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-bases]-biphenyl-4-yl }-NSC 4535: use 1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-bases]-biphenyl-4-yl according to the method described in embodiment 6 steps 4 }-cyclobutane carboxylate prepares.

Embodiment 8:1-{4 '-[4-(1-cyclohexyl-ethoxy carbonyl amino)-3-methyl-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of cyclopropane-carboxylic acid (compound 2)

Step 1: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine 1-cyclohexyl-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and 1-cyclohexyl ethyl alcohol to prepare according to the method described in embodiment 1 step 5.

Step 2:1-{4 '-[4-(1-cyclohexyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-base]-biphenyl-4-yl }-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine 1-cyclohexyl-ethyl ester and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 3:1-{4 '-[4-(1-cyclohexyl-ethoxy carbonyl amino)-3-methyl-isoxazole-5-base]-biphenyl-4-yl }-cyclopropane-carboxylic acid: use 1-{4 '-[4-(1-cyclohexyl-ethoxy carbonyl amino)-3-methyl-isoxazole-5-base]-biphenyl-4-yl according to the method described in embodiment 2 steps 8 }-the cyclopropane carboxylic acid acetoacetic ester prepares.

Embodiment 9:1-[4 '-(4-benzyl oxygen base carbonylamino-3-methyl-isoxazole-5-bases)-biphenyl-4-yl]-cyclopropane-carboxylic acid (compound 4) synthetic

Step 1: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine benzyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and benzylalcohol to prepare according to the method described in embodiment 1 step 5.

Step 2:1-[4 '-(4-benzyl oxygen base carbonylamino-3-methyl-isoxazole-5-base)-biphenyl-4-yl]-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine benzyl ester and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 3:1-[4 '-(4-benzyl oxygen base carbonylamino-3-methyl-isoxazole-5-base)-biphenyl-4-yl]-cyclopropane-carboxylic acid: use 1-[4 '-(4-benzyl oxygen base carbonylamino-3-methyl-isoxazole-5-base)-biphenyl-4-yl]-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 2 steps 8.

Embodiment 10: (S)-1-{4 '-and [4-(1-cyclopropyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of cyclopropane-carboxylic acid (compound 5)

According to the method described in embodiment 2 steps 8 use from embodiment 3a step 2 (1-{4 '-[4-(1-cyclopropyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-base]-biphenyl-4-yl-the cyclopropane carboxylic acid acetoacetic ester) enantiomer A prepare.

Embodiment 11:1-[4 '-(4-cyclo propyl methoxy carbonylamino-3-methyl-isoxazole-5-bases)-biphenyl-4-yl]-cyclopropane-carboxylic acid (compound 7) synthetic

Step 1: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine cyclopropyl methyl esters: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and cyclopropyl-carbinol to prepare according to the method described in embodiment 1 step 5.

Step 2:1-[4 '-(4-cyclo propyl methoxy carbonylamino-3-methyl-isoxazole-5-base)-biphenyl-4-yl]-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine cyclopropyl methyl esters and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 3:1-[4 '-(4-cyclo propyl methoxy carbonylamino-3-methyl-isoxazole-5-base)-biphenyl-4-yl]-cyclopropane-carboxylic acid: use 1-[4 '-(4-cyclo propyl methoxy carbonylamino-3-methyl-isoxazole-5-base)-biphenyl-4-yl]-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 2 steps 8.

Synthesizing of embodiment 12:1-(4 '-{ 4-[1-(2-methoxyl group-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 12)

Step 1: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine 1-(2-methoxyl group-phenyl)-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and 1-(2-p-methoxy-phenyl) ethanol to prepare according to the method described in embodiment 1 step 5.

Step 2:1-(4 '-{ 4-[1-(2-methoxyl group-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine 1-(2-methoxyl group-phenyl)-ethyl ester and 1-according to the method described in embodiment 6 steps 3; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 3:1-(4 '-{ 4-[1-(2-methoxyl group-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid synthetic: use 1-(4 '-{ 4-[1-(2-methoxyl group-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 6 steps 4.

Synthesizing of embodiment 13:1-(4 '-{ 3-methyl-4-[1-(4-trifluoromethyl-phenyl)-ethoxy carbonyl amino]-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 13)

Step 1: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine 1-(4-trifluoromethyl-phenyl)-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and 1-[4-(trifluoromethyl) phenyl] ethanol to prepare according to the method described in embodiment 1 step 5.

Step 2:1-(4 '-{ 3-methyl-4-[1-(4-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-base }-biphenyl-4-yl)-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine 1-(4-trifluoromethyl-phenyl)-ethyl ester and 1-according to the method described in embodiment 6 steps 3; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares; Use chiral column (95: 5 hexanes: EtOAc) come the isolated material of purifying, enantiomer A and enantiomer B are provided then through preparation property HPLC.Enantiomer A RT is 30 minutes, and enantiomer B RT is 50 minutes.

Step 3:1-(4 '-{ 3-methyl-4-[1-(4-trifluoromethyl-phenyl)-ethoxy carbonyl amino]-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: use enantiomer A to prepare from embodiment 13 steps 2 (1-(4 '-{ 3-methyl-4-[1-(4-trifluoromethyl-phenyl)-ethoxy carbonyl amino]-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester) according to the method described in embodiment 6 steps 4.

Synthesizing of embodiment 14:1-(4 '-{ 3-methyl-4-[1-(4-trifluoromethyl-phenyl)-ethoxy carbonyl amino]-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 14)

Use enantiomer B to prepare according to the method described in embodiment 6 steps 4 from embodiment 13 steps 2 (1-(4 '-{ 3-methyl-4-[1-(4-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester).

Synthesizing of embodiment 15:1-(4 '-{ 4-[1-(3-cyanic acid-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 15)

Step 1:3-(1-hydroxyl-ethyl)-benzonitrile: in the solution of 3-ethanoyl benzonitrile (1 equivalent) in methyl alcohol, add Peng Qinghuana (about 1.67 equivalents) in room temperature, and with reaction mixture stir about 20 minutes.Implement the water-based aftertreatment, title compound is provided.

Step 2: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine 1-(3-cyanic acid-phenyl)-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and 3-(1-hydroxyl-ethyl)-benzonitrile to prepare according to the method described in embodiment 1 step 5.

Step 3:1-(4 '-{ 4-[1-(3-cyanic acid-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine 1-(3-cyanic acid-phenyl)-ethyl ester and 1-according to the method described in embodiment 6 steps 3; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 4:1-(4 '-{ 4-[1-(3-cyanic acid-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: use 1-(4 '-{ 4-[1-(3-cyanic acid-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 6 steps 4.

Embodiment 16:1-{4 '-[3-methyl-4-((R)-1-is right-tolyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of cyclopropane-carboxylic acid (compound 16)

Step 1: (R)-1-is right-tolyl-ethanol: according to the method described in embodiment 2 steps 5 use 4 '-methyl acetophenone prepares.

Step 2: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-is right-tolyl-ethyl ester: according to the method described in embodiment 1 step 5 use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and (R)-1-right-tolyl-ethanol prepares.

Step 3:1-{4 '-[3-methyl-4-((R)-1-is right-tolyl-ethoxy carbonyl is amino)-isoxazole-5-base]-biphenyl-4-yl }-the cyclopropane carboxylic acid acetoacetic ester: according to the use of the method described in embodiment 6 steps 3 [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine (R)-1-right-[4-(4 for tolyl-ethyl ester and 1-; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 4:1-{4 '-[3-methyl-4-((R)-1-is right-tolyl-ethoxy carbonyl is amino)-isoxazole-5-base]-biphenyl-4-yl }-cyclopropane-carboxylic acid: use 1-{4 '-[3-methyl-4-((R)-1-right-tolyl-ethoxy carbonyl amino)-isoxazole-5-base]-biphenyl-4-yl according to the method described in embodiment 6 steps 4 }-the cyclopropane carboxylic acid acetoacetic ester prepares.

Embodiment 17:1-{4 '-[3-methyl-4-(between (R)-1--tolyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of cyclopropane-carboxylic acid (compound 17)

Step 1: (R)-1-between-tolyl-ethanol: according to the method described in embodiment 2 steps 5 use 3 '-methyl acetophenone prepares.

Step 2: between [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1--tolyl-ethyl ester: according to the method described in embodiment 1 step 5 use between 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and (R)-1--tolyl-ethanol prepares.

Step 3:1-{4 '-[3-methyl-4-(between (R)-1--tolyl-ethoxy carbonyl is amino)-isoxazole-5-base]-biphenyl-4-yl }-the cyclopropane carboxylic acid acetoacetic ester: according between the use of the method described in embodiment 6 steps 3 [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine (R)-1--[4-(4 for tolyl-ethyl ester and 1-; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 4:1-{4 '-[3-methyl-4-(between (R)-1--tolyl-ethoxy carbonyl is amino)-isoxazole-5-base]-biphenyl-4-yl }-cyclopropane-carboxylic acid: use 1-{4 '-[3-methyl-4-(between (R)-1--tolyl-ethoxy carbonyl amino)-isoxazole-5-base]-biphenyl-4-yl according to the method described in embodiment 6 steps 4 }-the cyclopropane carboxylic acid acetoacetic ester prepares.

Synthesizing of embodiment 18:1-(4 '-{ 4-[(R)-1-(4-cyanic acid-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 18)

Step 1:4-((R)-1-hydroxyl-ethyl)-benzonitrile: use 4-ethanoyl benzonitrile to prepare according to the method described in embodiment 2 steps 5.

Step 2: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-(4-cyanic acid-phenyl)-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and 4-((R)-1-hydroxyl-ethyl)-benzonitrile to prepare according to the method described in embodiment 1 step 5.

Step 3:1-(4 '-4-[(R)-1-(4-cyanic acid-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine (R)-1-(4-cyanic acid-phenyl)-ethyl ester and 1-according to the method described in embodiment 6 steps 3; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 4:1-(4 '-{ 4-[(R)-1-(4-cyanic acid-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: use 1-(4 '-{ 4-[(R)-1-(4-cyanic acid-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 6 steps 4.

Synthesizing of embodiment 19:1-(4 '-{ 4-[(R)-1-(2-cyanic acid-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 19)

Step 1:2-((R)-1-hydroxyl-ethyl)-benzonitrile: use 2-acetylbenzene formonitrile HCN to prepare according to the method described in embodiment 2 steps 5.

Step 2: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-(2-cyanic acid-phenyl)-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and 2-((R)-1-hydroxyl-ethyl)-benzonitrile to prepare according to the method described in embodiment 1 step 5.

Step 3:1-(4 '-4-[(R)-1-(2-cyanic acid-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine (R)-1-(2-cyanic acid-phenyl)-ethyl ester and 1-according to the method described in embodiment 6 steps 3; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 4:1-(4 '-{ 4-[(R)-1-(2-cyanic acid-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: use 1-(4 '-{ 4-[(R)-1-(2-cyanic acid-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 6 steps 4.

Embodiment 20:1-{4 '-[4-((R)-1-cyclobutyl-ethoxy carbonyl amino)-3-methyl-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of cyclopropane-carboxylic acid (compound 20)

Step 1: (R)-1-cyclobutyl-ethanol: use cyclobutylmethyl ketone to prepare according to the method described in embodiment 2 steps 5.

Step 2: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-cyclobutyl-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and (R)-1-cyclobutyl-ethanol to prepare according to the method described in embodiment 1 step 5.

Step 3:1-{4 '-[4-((R)-1-cyclobutyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-base]-biphenyl-4-yl }-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine (R)-1-cyclobutyl-ethyl ester and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 4:1-{4 '-[4-((R)-1-cyclobutyl-ethoxy carbonyl amino)-3-methyl-isoxazole-5-base]-biphenyl-4-yl }-cyclopropane-carboxylic acid: use 1-{4 '-[4-((R)-1-cyclobutyl-ethoxy carbonyl amino)-3-methyl-isoxazole-5-base]-biphenyl-4-yl according to the method described in embodiment 2 steps 8 }-the cyclopropane carboxylic acid acetoacetic ester prepares.

Synthesizing of embodiment 21:1-(4 '-{ 4-[1-(2-chloro-hexamethylene-1-thiazolinyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 21)

Step 1:2-chloro-hexamethylene-1-cyclohexene carboxaldehyde: room temperature to pimelinketone (1.34g, 13.6mmol) add in the solution in toluene DMF (1.58mL, 20.5mmol) and phosphoryl chloride (1.88mL, 20.5mmol).Reaction mixture in stirred overnight at room temperature, is used H then ₂The O dilution was also stirred 30 minutes.Add 4N NaOH solution (10mL), and extract mixture with EtOAc.The organic layer that merges is used saturated NH ₄The Cl solution washing is through MgSO ₄Drying is filtered and is concentrated, and obtains title compound.

Step 2:1-(2-chloro-hexamethylene-1-thiazolinyl)-ethanol: (3M is in THF in the 2-chloro-hexamethylene-solution of 1-cyclohexene carboxaldehyde (13.6mmol) in THF, to add methyl-magnesium-bromide at 0 ℃; 5.4mL, 16.32mmol).Under nitrogen, reaction mixture was stirred 1 hour, add iPrOH (2mL) then.Enriched mixture also extracts residue with 1N HCl aqueous solution dilution and with EtOAc.The organic layer that merges is used saturated NH ₄The Cl solution washing is through MgSO ₄Drying is filtered and is concentrated, and comes the thick material of purifying through silica gel chromatography, obtains title compound.

Step 3:5-[4 '-(1-ethoxy carbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazoles-4-formic acid: [4-(4 to use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 4:1-(4 '-{ 4-[1-(2-chloro-hexamethylene-1-thiazolinyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester: prepare according to the use of the method described in embodiment 1 step 5 5-[4 '-(1-ethoxy carbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-formic acid and 1-(2-chloro-hexamethylene-1-thiazolinyl)-ethanol.

Step 5:1-(4 '-{ 4-[1-(2-chloro-hexamethylene-1-thiazolinyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: use 1-(4 '-{ 4-[1-(2-chloro-hexamethylene-1-thiazolinyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 2 steps 8.

Synthesizing of embodiment 22:1-(4 '-{ 3-methyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 22)

Step 1: (R)-1-(3-trifluoromethyl-phenyl)-ethanol: according to the method described in embodiment 2 steps 5 use 3 '-(trifluoromethyl) methyl phenyl ketone prepares.

Step 2: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and (R)-1-(3-trifluoromethyl-phenyl)-ethanol to prepare according to the method described in embodiment 1 step 5.

Step 3:1-(4 '-3-methyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-base }-biphenyl-4-yl)-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester and 1-according to the method described in embodiment 6 steps 3; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 4:1-(4 '-{ 3-methyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: use 1-(4 '-{ 3-methyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl amino]-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 6 steps 4.

Synthesizing of embodiment 23:1-(4 '-{ 4-[(R)-1-(3-methoxyl group-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 23)

Step 1: (R)-1-(3-methoxyl group-phenyl)-ethanol: according to the method described in embodiment 2 steps 5 use 3 '-methoxyacetophenone prepares.

Step 2: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-(3-methoxyl group-phenyl)-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and (R)-1-(3-methoxyl group-phenyl)-ethanol to prepare according to the method described in embodiment 1 step 5.

Step 3:1-(4 '-4-[(R)-1-(3-methoxyl group-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine (R)-1-(3-methoxyl group-phenyl)-ethyl ester and 1-according to the method described in embodiment 6 steps 3; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 4:1-(4 '-{ 4-[(R)-1-(3-methoxyl group-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: use 1-(4 '-{ 4-[(R)-1-(3-methoxyl group-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 6 steps 4.

Synthesizing of embodiment 24:1-(4 '-{ 4-[(R)-1-(4-methoxyl group-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 24)

Step 1: (R)-1-(4-methoxyl group-phenyl)-ethanol: according to the method described in embodiment 2 steps 5 use 4 '-methoxyacetophenone prepares.

Step 2: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-(4-methoxyl group-phenyl)-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and (R)-1-(4-methoxyl group-phenyl)-ethanol to prepare according to the method described in embodiment 1 step 5.

Step 3:1-(4 '-4-[(R)-1-(4-methoxyl group-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine (R)-1-(4-methoxyl group-phenyl)-ethyl ester and 1-according to the method described in embodiment 6 steps 3; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 4:1-(4 '-{ 4-[(R)-1-(4-methoxyl group-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: use 1-(4 '-{ 4-[(R)-1-(4-methoxyl group-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 6 steps 4.

Synthesizing of embodiment 25:1-(4 '-{ 4-[1-(3-bromo-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 25)

Step 1:1-(4 '-{ 4-[1-(3-bromo-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester: prepare according to the use of the method described in embodiment 1 step 5 5-[4 '-(1-ethoxy carbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-formic acid and 3-bromo-α-Jia Jibianchun.

Step 2:1-(4 '-{ 4-[1-(3-bromo-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: use 1-(4 '-{ 4-[1-(3-bromo-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 2 steps 8.

Synthesizing of embodiment 26:1-(4 '-{ 4-[1-(3-chloro-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 26)

Step 1:1-(4 '-{ 4-[1-(3-chloro-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester: prepare according to the use of the method described in embodiment 1 step 5 5-[4 '-(1-ethoxy carbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-formic acid and 1-(3-chloro-phenyl-) ethanol.

Step 2:1-(4 '-{ 4-[1-(3-chloro-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: use 1-(4 '-{ 4-[1-(3-chloro-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 2 steps 8.

Embodiment 27:1-{4 '-[3-methyl-4-((S)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of cyclopropane-carboxylic acid (compound 27)

Step 1: (S)-[5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine 1-phenyl-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and (S)-1-phenylethyl alcohol (to be available commercially or to use the application's method described or in following document to prepare: E.J.Corey et al.J.Am.Chem.1987 for example according to the method described in embodiment 1 step 5; 109,5551-5553) prepare.

Step 2:1-{4 '-[3-methyl-4-((S)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-base]-biphenyl-4-yl }-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use (S)-[5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine 1-phenyl-ethyl ester and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 3:1-{4 '-[3-methyl-4-((S)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-base]-biphenyl-4-yl }-cyclopropane-carboxylic acid: use 1-{4 '-[3-methyl-4-((S)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-base]-biphenyl-4-yl according to the method described in embodiment 2 steps 8 }-the cyclopropane carboxylic acid acetoacetic ester prepares.

Synthesizing of embodiment 28:1-(4 '-{ 4-[1-(3-hydroxyl-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 28)

Step 1:1-[3-(tertiary butyl-dimethyl--silyl oxygen base)-phenyl]-ethyl ketone: to 3 '-hydroxy acetophenone (0.500g, 3.67mmol) and imidazoles (0.500g is 7.34mmol) in CH ₂Cl ₂Add in the solution (5mL) tert-butyldimethylsilyl chloride (0.609g, 4.04mmol), and with reaction mixture stirring at room 1 hour.Mixture is allocated in CH ₂Cl ₂With H ₂Between the O, and isolate water layer and use CH ₂Cl ₂Extraction.With the organic layer that merges through MgSO ₄Drying is filtered and is concentrated, and obtains title compound.

Step 2:1-[3-(tertiary butyl-dimethyl--silyl oxygen base)-phenyl]-ethanol: (0.139g 3.67mmol) handles with Peng Qinghuana with 1-[3-(tertiary butyl-dimethyl--silyl oxygen base)-the phenyl]-solution of ethyl ketone (3.67mmol) in MeOH (5mL).Reaction mixture was stirred 20 minutes, and implementation criteria aftertreatment then provides title compound.

Step 3: [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine 1-[3-(tertiary butyl-dimethyl--silyl oxygen base)-phenyl]-ethyl ester: use 5-(4-bromo-phenyl)-3-methyl-isoxazoles-4-formic acid and 1-[3-(tertiary butyl-dimethyl--silyl oxygen base)-phenyl]-ethanol to prepare according to the method described in embodiment 1 step 5.

Step 4:1-[4 '-(4-{1-[3-(tertiary butyl-dimethyl--silyl oxygen base)-phenyl]-ethoxy carbonyl is amino }-3-methyl-isoxazole-5-base)-biphenyl-4-yl]-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine 1-[3-(tertiary butyl-dimethyl--silyl oxygen base)-phenyl]-ethyl ester and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1; 3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 5:1-(4 '-{ 4-[1-(3-hydroxyl-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: with 1-[4 '-(4-{1-[3-(tertiary butyl-dimethyl--silyl oxygen base)-phenyl]-ethoxy carbonyl amino }-3-methyl-isoxazole-5-base)-biphenyl-4-yl]-(0.400g is 0.63mmol) 3: 1MeOH: H for the cyclopropane carboxylic acid acetoacetic ester ₂Solution among the O (10mL) is handled with excessive Lithium Hydroxide MonoHydrate.With reaction mixture 60 ℃ of stirred overnight, acidifying and extract then with EtOAc.With the organic layer that merges through MgSO ₄Drying is filtered and is concentrated, and comes the purifying residue through preparation property HPLC, obtains title compound.

Embodiment 29:1-{4 '-[3-ethyl-4-((R)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of cyclopropane-carboxylic acid (compound 29)

Step 1:2-(4-bromo-benzoyl-)-3-oxo-methyl valerate: use 4-bromo-benzoyl chloride and 3-oxopentanoic acid methyl esters to prepare according to the method described in embodiment 1 step 2; Use sodium tert-butoxide to replace pyridine.

Step 2:5-(4-bromo-phenyl)-3-ethyl-isoxazoles-4-methyl-formiate: use 2-(4-bromo-benzoyl-)-3-oxo-methyl valerate and hydroxy amine hydrochloric acid salt to prepare according to the method described in embodiment 1 step 3.

Step 3:5-(4-bromo-phenyl)-3-ethyl-isoxazoles-4-formic acid: use 5-(4-bromo-phenyl)-3-ethyl-isoxazoles-4-methyl-formiate to prepare according to the method described in embodiment 1 step 4.

Step 4: [5-(4-bromo-phenyl)-3-ethyl-isoxazole-4-bases]-carboxylamine (R)-1-phenyl-ethyl ester: use following starting substance to prepare according to the method described in embodiment 1 step 5: 5-(4-bromo-phenyl)-3-ethyl-isoxazoles-4-formic acid reaches (R)-1-phenyl-ethanol.

Step 5:1-{4 '-[3-ethyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-base]-biphenyl-4-yl }-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-ethyl-isoxazole-4-base]-carboxylamine (R)-1-phenyl-ethyl ester and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 6:1-{4 '-[3-ethyl-4-((R)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-base]-biphenyl-4-yl }-cyclopropane-carboxylic acid: use 1-{4 '-[3-ethyl-4-((R)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-base]-biphenyl-4-yl according to the method described in embodiment 2 steps 8 }-the cyclopropane carboxylic acid acetoacetic ester prepares.

Synthesizing of embodiment 30:1-(4 '-{ 3-ethyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 30)

Step 1: [5-(4-bromo-phenyl)-3-ethyl-isoxazole-4-bases]-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester: use 5-(4-bromo-phenyl)-3-ethyl-isoxazoles-4-formic acid and (R)-1-(3-trifluoromethyl-phenyl)-ethanol to prepare according to the method described in embodiment 1 step 5.

Step 2:1-(4 '-3-ethyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-base }-biphenyl-4-yl)-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-phenyl)-3-ethyl-isoxazole-4-base]-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 3:1-(4 '-{ 3-ethyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: use 1-(4 '-{ 3-ethyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl amino]-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 2 steps 8.

Embodiment 31:1-{4 '-[3-methyl-4-((1-phenyl-oxyethyl group-d9)-carbonylamino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid synthetic

Step 1:1-{4 '-[3-methyl-4-((1-phenyl-oxyethyl group-d9)-carbonylamino)-isoxazole-5-base]-biphenyl-4-yl }-the cyclopropane carboxylic acid acetoacetic ester: use 5-[4 '-(1-ethoxy carbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-formic acid and 1-phenylethyl alcohol-d9 (by the deuterium of Carbocore acquisition for the 1-phenylethyl alcohol) to prepare according to the method described in embodiment 1 step 5.

Step 2: use 1-{4 '-[3-methyl-4-((1-phenyl-oxyethyl group-d9)-carbonylamino)-isoxazole-5-base]-biphenyl-4-yl according to the method described in embodiment 2 steps 8 }-the cyclopropane carboxylic acid acetoacetic ester prepares.

Embodiment 32:1-(3 '-methoxyl group-4 '-{ 3-methyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-bases }-biphenyl-4-yl)-the synthesizing of cyclopropane-carboxylic acid (compound 31)

Step 1:4-bromo-2-methoxyl group-Benzoyl chloride 99min.: (2.5g is 11.04mmol) in CHCl to 4-bromo-O-Anisic Acid ₃Add in the suspension (20mL) DMF (catalysis) and THIONYL CHLORIDE 97 (1.6mL, 22.08mmol).Reaction mixture is concentrated into drying in 1 hour then 55 ℃ of stirrings, obtains title compound.

Step 2:2-(4-bromo-2-methoxyl group-benzoyl-)-3-oxo-methyl-butyrate: use 4-bromo-2-methoxyl group-Benzoyl chloride 99min. and 3-methylamino amino-but-2-ene acid methyl esters to prepare according to the method described in embodiment 1 step 2.

Step 3:5-(4-bromo-2-methoxyl group-phenyl)-3-methyl-isoxazoles-4-methyl-formiate: use 2-(4-bromo-2-methoxyl group-benzoyl-)-3-oxo-methyl-butyrate and hydroxy amine hydrochloric acid salt to prepare according to the method described in embodiment 1 step 3.

Step 4:5-(4-bromo-2-methoxyl group-phenyl)-3-methyl-isoxazoles-4-formic acid: use 5-(4-bromo-2-methoxyl group-phenyl)-3-methyl-isoxazoles-4-methyl-formiate to prepare according to the method described in embodiment 1 step 4.

Step 5: [5-(4-bromo-2-methoxyl group-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester: use 5-(4-bromo-2-methoxyl group-phenyl)-3-methyl-isoxazoles-4-formic acid and (R)-1-(3-trifluoromethyl-phenyl)-ethanol to prepare according to the method described in embodiment 1 step 5.

Step 6:1-(3 '-methoxyl group-4 '-3-methyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-base }-biphenyl-4-yl)-the cyclopropane carboxylic acid acetoacetic ester: [4-(4 to use [5-(4-bromo-2-methoxyl group-phenyl)-3-methyl-isoxazole-4-base]-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1; 3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the cyclopropane carboxylic acid acetoacetic ester prepares.

Step 7:1-(3 '-methoxyl group-4 '-{ 3-methyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: according to the method described in embodiment 2 steps 8 use 1-(3 '-methoxyl group-4 '-{ 3-methyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl amino]-isoxazole-5-base }-biphenyl-4-yl)-the cyclopropane carboxylic acid acetoacetic ester prepares.

Synthesizing of embodiment 33:1-(4 '-{ 4-[(R)-1-(3,5-two bromo-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 32)

Step 1:1-(3,5-two bromo-phenyl)-ethyl ketone: 0 ℃ to 3, (2.5g is 8.9mmol) in Et for the 5-dibromobenzoic acid ₂(1.6M is at Et dropwise to add lithium methide in the solution among the O (30mL) ₂Among the O; 12.3mL, 19.6mmol).Reaction mixture was stirred 2 hours at 0 ℃, handle with the EtOAc and the 10%HCl aqueous solution then.Come the thick material of purifying through silica gel chromatography, obtain title compound.

Step 2: (R)-1-(3,5-two bromo-phenyl)-ethanol: use 1-(3,5-two bromo-phenyl)-ethyl ketone to prepare according to the method described in embodiment 2 steps 5.

Step 3:1-(4 '-4-[(R)-1-(3; 5-two bromo-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base-biphenyl-4-yl)-the cyclopropane carboxylic acid acetoacetic ester: according to the method described in embodiment 1 step 5 use 5-[4 '-(1-ethoxy carbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-formic acid reach (R)-1-(3,5-two bromo-phenyl)-ethanol prepares.

Step 4:1-(4 '-4-[(R)-1-(3; 5-two bromo-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid: use 1-(4 '-{ 4-[(R)-1-(3,5-two bromo-phenyl)-ethoxy carbonyl amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane carboxylic acid acetoacetic ester to prepare according to the method described in embodiment 2 steps 8.

Embodiment 34:{5-[4 '-(1-methylsulfonyl aminocarboxyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-phenyl-ethyl ester (compound 35) synthetic

Make 1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid (0.1g; 0.2mmol), Toluidrin (0.08g; 0.8mmol) and N, (0.15g 0.6mmol) mixes in THF (4mL) N '-carbonyl dimidazoles.Add diisopropyl ethyl amine (0.5mL), and with reaction mixture 65 ℃ of stirred overnight.With the mixture acidifying and use CH ₂Cl ₂Extraction.(among the 0-50%EtOAc in hexane) comes the thick material of purifying through silica gel chromatography, obtains title compound.

Embodiment 35:{5-[4 '-(1-benzenesulfonyl aminocarboxyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-phenyl-ethyl ester (compound 36) synthetic

Use 1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl according to the method described in embodiment 34 steps 1 }-cyclopropane-carboxylic acid and benzsulfamide prepare.

Embodiment 36:{5-[4 '-(1-cyanic acid-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-phenyl-ethyl ester (compound 37) synthetic

Step 1:1-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-Trimetylene formonitrile HCN: use 1-(4-bromo-phenyl)-Trimetylene formonitrile HCN and couplet boric acid two pinacol esters to prepare according to the method described in embodiment 2 steps 4.

Step 2:{5-[4 '-(1-cyanic acid-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-phenyl-ethyl ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-phenyl-ethyl ester and 1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-the Trimetylene formonitrile HCN prepares.

Embodiment 37: (3-methyl-5-{4 '-[1-(5-oxo-2,5-dihydro-[1,2,4] oxadiazole-3-yls)-cyclopropyl]-biphenyl-4-yl }-isoxazole-4-bases)-carboxylamine (R)-1-phenyl-ethyl ester (compound 38) synthetic

Step 1: (5-{4 '-[1-(N-hydroxy formamidine base)-cyclopropyl]-biphenyl-4-yl }-3-methyl-isoxazole-4-bases)-carboxylamine (R)-1-phenyl-ethyl ester: make 5-[4 '-(1-cyanic acid-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-phenyl-ethyl ester (0.307g; 0.66mmol), hydroxy amine hydrochloric acid salt (0.046g; 0.67mmol) and triethylamine (0.097mL; 0.67mmol) in EtOH (7mL), mix, and with reaction mixture 50 ℃ of stirred overnight.Add extra hydroxy amine hydrochloric acid salt (0.100g, 1.45mmol) and triethylamine (0.30mL, 2.15mmol), and with the reaction mixture stirred overnight.Enriched mixture provides title compound then.

Step 2: (3-methyl-5-{4 '-[1-(5-oxo-2; 5-dihydro-[1; 2,4] oxadiazole-3-yl)-cyclopropyl]-biphenyl-4-yl }-isoxazole-4-bases)-carboxylamine (R)-1-phenyl-ethyl ester: to (5-{4 '-[1-(N-hydroxy formamidine base)-cyclopropyl]-biphenyl-4-yl }-3-methyl-isoxazole-4-bases)-carboxylamine (R)-1-phenyl-ethyl ester (0.66mmol) is at CH ₂Cl ₂Add in the solution (5mL) triethylamine (0.19mL, 1.32mmol) and Vinyl chloroformate (0.127mL, 1.32mmol), and with reaction mixture in stirred overnight at room temperature.(0.19mL 1.32mmol), and stirs reaction mixture 6 hours to add extra triethylamine.(0.19mL 1.32mmol), and stirs until reaction and accomplishes to add extra triethylamine.Mixture is used CH ₂Cl ₂(20mL) dilution and wash with 10% aqueous citric acid solution is then through MgSO ₄Dry, filtration and concentrated.Residue is dissolved in toluene (10mL), and solution was refluxed 3 days.After concentrating, (among the 0-100%EtOAc in hexane) comes the thick material of purifying through silica gel chromatography, obtains title compound.

Embodiment 38: (3-methyl-5-{4 '-[1-(1H-tetrazolium-5-yl)-cyclopropyl]-biphenyl-4-yl }-isoxazole-4-bases)-carboxylamine (R)-1-phenyl-ethyl ester (compound 39) synthetic

Make 5-[4 '-(1-cyanic acid-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-phenyl-ethyl ester (0.385g; 0.83mmol) and N; (0.101mL 1.0mmol) mixes in (2mL) at diethylene glycol dimethyl ether (diglyme) the N-dimethylethanolamine.(4M is 1, in the 4-diox to add hydrochloric acid; 4.2mL), and with reaction mixture stirring 15 minutes.Add extra N, (0.221mL, 2.2mmol), (0.098g 1.5mmol), and stirs reaction mixture 24 hours at 120 ℃ the N-dimethylethanolamine to add sodiumazide subsequently.After being cooled to room temperature, use CH ₂Cl ₂(20mL) and H ₂O (10mL) diluted mixture thing.With organic layer through MgSO ₄Drying is filtered and is concentrated, and comes the purifying residue through silica gel chromatography, obtains title compound.

Embodiment 39:{5-[4 '-(1-methylsulfonyl aminocarboxyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester (compound 40) synthetic

Step 1:N-[1-(4-bromo-phenyl)-cyclopropane carbonyl]-Toluidrin: to 1-(4-bromo-phenyl)-cyclopropane-carboxylic acid (5.0g; 20.7mmol) slowly add THIONYL CHLORIDE 97 (17.7mL in the solution in toluene (30mL); 243mmol), and with reaction mixture refluxed 4 hours.Enriched mixture, and thick material dissolved in toluene (50mL).(11.41g 120mmol), adds triethylamine (15mL) subsequently, and with reaction mixture refluxed 3 hours to add Toluidrin.After being cooled to room temperature, pour mixture into CH ₂Cl ₂(200mL) and use H ₂O (150mL) washing.With organic layer through MgSO ₄Drying, filtration also concentrate, and come the thick material of purifying through silica gel chromatography, obtain title compound.

[4-(4 for step 2:N-{1-; 4; 5; 5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-cyclopropane carbonyl }-Toluidrin: use N-[1-(4-bromo-phenyl)-cyclopropane carbonyl]-Toluidrin and couplet boric acid two pinacol esters to prepare according to the method described in embodiment 2 steps 4.

Step 3:{5-[4 '-(1-methylsulfonyl aminocarboxyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester: [4-(4 to use [5-(4-bromo-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester and N-{1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1; 3,2] dioxo bora pentamethylene-2-yl)-phenyl]-cyclopropane carbonyl }-Toluidrin prepares.

Embodiment 40:{5-[4 '-(1-methylsulfonyl aminocarboxyl-cyclopropyl)-3-methoxyl group-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester (compound 41) synthetic

Step 1: [5-(4-bromo-2-methoxyl group-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester: use 5-(4-bromo-2-methoxyl group-phenyl)-3-methyl-isoxazoles-4-formic acid and (R)-1-(3-trifluoromethyl-phenyl)-ethanol to prepare according to the method described in embodiment 1 step 5.

Step 2:{5-[4 '-(1-methylsulfonyl aminocarboxyl-cyclopropyl)-3-methoxyl group-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester: [4-(4 to use [5-(4-bromo-2-methoxyl group-phenyl)-3-methyl-isoxazole-4-bases]-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester and N-{1-according to the method described in embodiment 1 step 6; 4; 5; 5-tetramethyl--[1; 3,2] dioxo bora pentamethylene-2-yl)-phenyl]-cyclopropane carbonyl }-Toluidrin prepares.

Embodiment 41:1-{4 '-[4-((R)-1-phenyl-ethoxy carbonyl amino)-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of cyclopropane-carboxylic acid (compound 33)

Step 1:5-(4-bromo-phenyl)-isoxazoles-4-ethyl formate: (1.19g, 4.39mmol) in N, the solution in the dinethylformamide dimethylacetal (10mL) stirred 1 hour at 100 ℃ with (4-benzoyl bromide) ETHYLE ACETATE.Enriched mixture, and residue dissolved in EtOAc (10mL).(0.454g 6.57mmol), and stirs reaction mixture 1 hour at 100 ℃ to add hydroxy amine hydrochloric acid salt.After being cooled to room temperature, mixture is allocated in EtOAc and H ₂Between the O, and isolate organic layer, through MgSO ₄Drying is filtered and is concentrated.Come the thick material of purifying through silica gel chromatography, obtain title compound.

Step 2:5-(4-bromo-phenyl)-isoxazoles-4-formic acid: (0.500g is 1.69mmol) at concentrated hydrochloric acid (2mL), acetate (5mL) and H with 5-(4-bromo-phenyl)-isoxazoles-4-ethyl formate ₂Dissolving among the O (5mL), and with reaction mixture 100 ℃ of stirred overnight.Mixture is allocated in EtOAc and H ₂Between the O, and isolate organic layer, through MgSO ₄Drying is filtered and is concentrated, and obtains title compound.

Step 3: [5-(4-bromo-phenyl)-isoxazole-4-bases]-carboxylamine (R)-1-phenyl-ethyl ester: use 5-(4-bromo-phenyl)-isoxazoles-4-formic acid and (R)-1-phenyl-ethanol to prepare according to the method described in embodiment 1 step 5.

Step 4:1-{4 '-[4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid: use [5-(4-bromo-phenyl)-isoxazole-4-bases]-carboxylamine (R)-1-phenyl-ethyl ester and 4-(1-carboxyl cyclopropyl) phenyl-boron dihydroxide to prepare according to the method described in embodiment 1 step 6.

Embodiment 42:1-{4 '-[3-methyl-4-(1-phenyl-ethoxy carbonyl amino)-isoxazole-5-bases]-biphenyl-4-yl }-the synthesizing of cyclopropane-carboxylic acid (compound 34)

According to embodiment 1 to compound 1 described method but use racemic 1-phenylethyl alcohol to replace (R)-(+)-1-phenylethyl alcohol to prepare.

In some embodiments, obtain mass-spectrometric data (mass spectrometric data, mass spec.data) through Shimadzu LCMS 2010A.

Embodiment 43: the human LPA of stably express ₁The foundation of Chinese hamster ovary celI system

By the human LPA of human lung clones coding ₁The 1.1kb cDNA of acceptor.Use the human lung RNA of RETROscript test kit (Ambion company) rt (Clontech Laboratories company, USA) and the PCR through reverse transcription reaction obtain human LPA ₁Full-length cDNA.Confirm the LPA that clones humans through checking order ₁Nucleotide sequence and confirm and disclose human LPA ₁Sequence identical (people such as An, Biochem.Biophys.Res.Commun.231:619 (1997)).CDNA is cloned in the pCDNA5/FRT expression plasmid and uses lipofectamine 2000 (Invitrogen company, USA) transfection in Chinese hamster ovary celI.Use Totomycin (hygromycin) to select the human LPA of stably express ₁Clone and being identified as show the cell that the Ca that replys with LPA flows into.

Embodiment 44: the human LPA of transient expression ₂The generation of cell

Obtain to contain human LPA by Missouri S&T cDNA Resource Center (www.cdna.org) ₂The carrier of receptor cdna.Obtain human LPA through PCR by carrier ₂The full-length cDNA fragment.Confirm the LPA that clones humans through checking order ₂Nucleotide sequence and confirm and disclose human LPA ₂Sequence identical (NCBI searching number NM_004720).CDNA is cloned in the pCDNA3.1 expression plasmid, and through be coated with gather-96 orifice plates of D-Methionin in 30,000-35,000 cells/well inoculating cell and 0.2 μ l lipofectamine 2000 and 0.2 μ g LPA ₂Expression vector with this plasmid transfection to B103 cell (Invitrogen company, USA) in.Before the Ca-that mensuration LPA brings out flows into, with cell overnight cultures in perfect medium.

Embodiment 45: the stable human LPA that expresses ₃The foundation of Chinese hamster ovary celI system

Obtain to contain human LPA by Missouri S&T cDNA Resource Center (www.cdna.org) ₃The carrier of receptor cdna.Obtain human LPA through PCR by carrier ₃The full-length cDNA fragment.Confirm the LPA that clones humans through checking order ₃Nucleotide sequence and confirm and disclose human LPA ₃Sequence identical (NCBI searching number NM_012152).CDNA is cloned in the pCDNA5/FRT expression plasmid and uses lipofectamine 2000 (Invitrogen company, USA) transfection in Chinese hamster ovary celI.Use Totomycin to select the human LPA of stably express ₃Clone and being identified as show the cell that the Ca that replys with LPA flows into.

Embodiment 46:LPA1 and LPA3 calcium current go into to measure

Measuring the human LPA that will express previous day or two days Chinese hamster ovary celI ₁Or LPA ₃With 20,000-45,000 cells/well be inoculated in be coated with gather-96 orifice plates of D-Methionin in.Before measuring, cell is washed once overnight cultures in serum free medium then with PBS.Measuring the same day, in each hole, be added in the mensuration damping fluid and (have Ca ²⁺And Mg ²⁺HBSS and contain 20mM Hepes and the human serum albumin of 0.3% FAF) in calconcarboxylic acid dyestuff (Calcium 4, Molecular Devices) and continue to cultivate 1 hour in 37 ℃.In each hole, add 10 μ l in 2.5%DMSO test compounds and continue to cultivate 30 minutes in room temperature.Through adding 10nM LPA irritation cell and using Flexstation 3 (Molecular Devices) to measure Ca in the cell ²⁺Make the Graphpad prism of medicament titration curve analyze definite IC ₅₀

Embodiment 47:LPA2 calcium current goes into to measure

The human breast cancer cell of BT-20 is with 25,000-35,000 cells/well in 150 μ l perfect mediums, be inoculated in be coated with gather-plate of the black wall clear bottom of D-Methionin on.After overnight cultures, with cell once, before measuring, make serum starvation 4-6 hour then with the PBS washing.Measuring the same day, in each hole, be added in the mensuration damping fluid and (have Ca ²⁺And Mg ²⁺HBSS and contain 20mM Hepes and the human serum albumin of 0.3% FAF) in calconcarboxylic acid dyestuff (Calcium 5, Molecular Devices) and continue to cultivate 15 minutes in 37 ℃.In each hole, add 25 μ l in 2.5%DMSO test compounds and continue to cultivate 15 minutes in 37 ℃.Through adding 100nM LPA irritation cell and using Flexstation 3 (Molecular Devices) to measure Ca in the cell ²⁺Make the Symyx Assay Explorer of medicament titration curve analyze definite IC ₅₀

Embodiment 48:GTP γ S combines to measure

Measure assessment compound inhibition GTP through film GTP γ S and be bonded to LPA ₁Ability.With stably express recombinant human LPA ₁The Chinese hamster ovary celI resuspending of acceptor in the 10mM Hepes that contains 1mM DTT (the pH value is 7.4), cracking and 75, centrifugal under the 000xg so that the film deposition.With each film resuspending in the 10mM Hepes that contains 1mM DTT and 10% glycerine (the pH value is 7.4).(50mM Hepes, pH 7.4,100mM NaCl, 10mM MgCl for mensuration damping fluid in 96 orifice plates ₂, 50 μ g/ml saponin(es and 0.2% FAF the human serum albumin) in each film (about 25 μ g/ holes) and 0.1nM [ ³⁵S]-GTP γ S, 900nM LPA, 5 μ M GDP and test compounds cultivated 30 minutes in 30 ℃ together.Filter termination reaction fast through Whatman GF/B spun glass filter plate.With filter plate with the cold lavation buffer solution of 1ml (50mM Hepes, 7.5,100mM NaCl and 10mM MgCl ₂) washing 3 times and dry.The radioactivity that in each plate, adds scintillator then and on upward definite each filter plate of Packard TopCount (Perkin Elmer), kept.The gross activity that specificity is combined to confirm as under no part (900nM LPA) situation combines to deduct non-specific binding.Make the Graphpad prism of medicament titration curve analyze definite IC ₅₀

Provide the Illustrative external biological data of the representative compound of formula (I) in the following table.

Compound number	HLPA1Ca flows into IC ₅₀	HLPA3Ca flows into IC ₅₀
			1	A	C
2	A	C
			3	A	B

Compound number	HLPA1Ca flows into IC ₅₀	HLPA3Ca flows into IC ₅₀
			4	A	D
5	C	ND
			6	A	D
7	A	D
			8	A	B
9	A	C
			10	A	C
11	A	C
			12	A	ND
13	C	ND
			14	A	C
15	A	C
			16	A	C
17	A	B
			18	A	C
19	A	C
			20	A	C
21	A	A
			22	A	A
23	A	C
			24	A	D
25	A	B
			26	A	B
27	A	D
			28	A	D
29	A	B
			30	A	A
31	A	A
			32	A	C
33	A	C
			34	A	C
35	A	C
			36	A	C
37	C	D
			38	A	C
39	A	C
			40	A	B
41	A	B

A=is less than 0.3 μ M; B=is greater than 0.3 μ M and less than 1 μ M;

C=is greater than 1 μ M and less than 10 μ M; D=is greater than 10 μ M.

ND=does not confirm

Embodiment 49:LPA1 chemotaxis is measured

Use Neuroprobe Chemo

System plate (aperture is 8 μ m, and the site diameter is 5.7mm) to measure the chemotaxis of the human MC of A2058.Apply 0.001% fibronectin (Sigma) among the 20mM Hepes (pH 7.4) and make its drying in the filter disc site.Make A2058 cell serum starvation 24 hours, collect with the cell stripper then and resuspending in the DMEM of the bovine serum albumin that contains 0.1% FAF (BSA) to 1 * 10 ⁶The concentration of/ml.With cell and isopyknic test compounds (2X) mixed 37 ℃ of cultivations 15 minutes that are incorporated in the DMEM of the BSA that contains 0.1% FAF.LPA (100nM is in the DMEM of the BSA that contains 0.1% FAF) or vehicle are added in each hole of lower floor and and are applied in the top of ChemoTx plate 50 μ l cell suspension/test compounds mixtures.Each plate is cultivated 3 hours then through with PBS drip washing and swipe by the top emigrated cells at 37 ℃.Dry filter disc uses HEMA 3 coloring systemss (Fisher Scientific) that it is dyeed then.Read the absorbancy of filter disc and use Symyx Assay Explorer to confirm IC at 590nM ₅₀

In this experiment, compound 1,4,8,16,17,19,21,29,35,36,38,39 suppresses the chemotaxis (IC of the LPA driving of human A2058 MC ₅₀Less than 100nM).

Embodiment 50: the pulmonary fibrosis model that bleomycin brings out in the mouse

(Harlan 25-30g), makes its ad lib and drinking-water and before the test beginning, makes it adapt at least 7 days 4 female C57Bl/6 mouse of each cage stable breeding.After the adaptive phase, with isoflurane (5%, at 100%O ₂In) slight anesthetized mice and through intratracheal instillation administration BLEOMYCIN SULPHATE (0.01-5U/kg, Henry Schein) (people Am J Physiol Lung Cell Mol Physiol.2007 such as Cuzzocrea S May; 292 (5): L1095-104.Epub on January 12nd, 2007).With mouse put back in its cage and in experimentation every day monitor.Every day oral administration, through intraperitoneal or subcutaneous delivery test compounds or vehicle.Route of administration and frequency are based on the previous pharmacokinetic property of confirming.After 3 days, 7 days, 14 days, 21 days or 28 days, utilization can suck isoflurane and put to death all animals at the instillation bleomycin.After execution, mouse is carried out intubate with No. 20 vessel catheters that are connected to the 1ml syringe.With salt solution lavation lung to obtain BAL fluid (BALF) and shift out then and to be fixed in 10% neutral buffered formalin (formalin) to be used for follow-up histopathological analysis.With BALF in centrifugal 10 minutes of 800 * g so that cell precipitation and emigrated cells supernatant and freezing to use DC protein determination kit (Biorad in-80 ℃; Hercules; CA.) (Biocolor ltd UK) carries out the soluble collagen analysis to carry out follow-up analysis of protein and use Sircol.Use the concentration of the inflammatory of commercially available elisa assay BALF, short fibrosis and tissue injury biomarker (comprising transforminggrowthfactor-, mucinase, tissue depressant, IGFBP-rP2 and the lactate dehydrogenase activity of metalloprotease-1, matrix metalloproteinase-7).Cell precipitation is suspended among the PBS again.(Drew Scientific, Wayne PA.) obtain total cell count and use Shandon cytospin (Thermo Scientific, Waltham MA.) confirm the difference cell counting to use Hemavet hematology system then.Use phenodin (hematoxylin) and Yihong (eosin) (H&E) and the trichrome stain agent is dyeed to lung tissue and carry out sxemiquantitative histopathology mark (people such as Ashcroft T., J.Clin.Path.1988 through use opticmicroscope (amplifying 10 times); 41; 4,467-470) and through using opticmicroscope that the collagen in the lung tissue section is carried out computer assisted density measurement confirm pulmonary fibrosis.Use Graphpad prism that data are drawn and definite respectively significant difference between group.

In acute setting (3 days), compound 1 significantly reduces total protein and the collagen concentration in the BAL fluid (BALF).In 7 days bleomycin models, compound 1 reduces BALF collagen, albumen, TGF β 1, MMP-7, hyaluronan and inflammatory cell and flows into.In chronic setting (14 days bleomycin models), when with precautionary approach (the 0th day the-the 14th day) or with therapeutic modality (the 3rd day the-the 14th day) administration, compound 1 reduces total lung collagen.

Embodiment 51: mouse carbon tetrachloride (CCl ₄) Liver Fibrosis Model of bringing out

(Harlan 20-25g), makes its ad lib and drinking-water and before the test beginning, makes it adapt at least 7 days 4 female C57BL/6 mouse of each cage stable breeding.After the adaptive phase, mouse is accepted in the CCl that dilutes in the Semen Maydis oil vehicle (100 μ L volume) through intraperitoneal injection ₄(1.0ml/kg body weight) biweekly, carried out for 8 weeks.(Higazi, people such as A.A., Clin Exp Immunol.2008 April; 152 (1): 163-73.Epub on February 14th, 2008).Control mice is only accepted isopyknic Semen Maydis oil vehicle.Every day oral administration, through intraperitoneal or subcutaneous delivery test compounds or vehicle.(intraperitoneal injection CCl first when research finishes ₄8 weeks of back), utilization can suck isoflurane execution mouse and gather blood to be used for the subsequent analysis of ALT/AST level through the heart puncture.Collect liver, and half liver is freezing and second half is fixed in 10% neutral buffered formalin so that the Histological assessment that carries out hepatic fibrosis with opticmicroscope (amplifying 10 times) at-80 ℃.Use Sircol (Biocolor ltd, UK) the collagen level of analysis liver tissue homogenate.Use h and E (H&E) and the trichrome stain agent is dyeed to the fixed hepatic tissue and confirm hepatic fibrosis through using opticmicroscope that the collagen in the hepatic tissue section is carried out computer assisted density measurement.Also use the concentration of the inflammatory of commercially available elisa assay blood plasma and hepatic tissue lysate, short fibrosis and tissue injury biomarker (tissue depressant, IGFBP-rP2 and the lactate dehydrogenase activity that comprise transforminggrowthfactor-, mucinase, metalloprotease-1, matrix metalloproteinase-7).Use Graphpad prism that the gained data are drawn and definite respectively significant difference between group.

In this experiment, to compare with not treatment group, compound 1 significantly reduces the collagen deposition in increase of liver weight and the liver.

Embodiment 52: the histamine release that LPA brings out in the mouse vein

Utilize the histamine release model that LPA brings out in the mouse vein to confirm LPA ₁And LPA ₃Effect in the body of receptor antagonist.Excite (300 μ g/ mouse are in 0.1%FAF BSA) 30 minutes before to 24 hours at intravenously LPA, to the compound (through intraperitoneal, subcutaneous or oral) of female CD-1 mouse (body weight is the 25-35 gram) administration 10ml/kg volume.After LPA excites, be positioned over mouse in the airtight Plexiglas chamber immediately and be exposed to the period that isoflurane reaches 2 minutes.It is taken out, broken end and with the trunk blood collection to the pipe that contains EDTA.Then 4 ℃ with blood with 10, centrifugal 10 minutes of 000X g.Confirm the histamine concentration in the blood plasma through EIA.Confirm the drug level in the blood plasma through mass spectrum.Through non-linear regression (Graphpad Prism) calculate to realize 50% suppress dosage that blood histamine discharges and with it as ED ₅₀Draw.Plasma concns that will be relevant with this dosage is as EC ₅₀Draw.

Embodiment 53: mouse corium vascular leakage is measured

Make female BALB/c mouse (Harlan) (heavy 20-25 gram) ad lib standard mouse feed and drinking-water and before the research beginning, make it adapt to for two weeks.Compound 1 prepared at concentrations and administered through oral gavage with 3mg/ml in water vehicle sent to produce the dosage of 30mg/kg with the 10ml/kg volume.After administration three hours, mouse is positioned in the limiting device and gives and ivens (the blue dyestuff (0.2ml 0.5% solution) of Evan ' s) through intravenously through tail vein injection.Use 3% isoflurane anesthesia agent anesthetized mice with through intradermal injection LPA (30 μ g are in the BSA of 20 μ l, 0.1% FAF) then.Injecting LPA after 30 minutes, through CO ₂Suck to put to death mouse and take off the skin that excites the position and be positioned in the 2ml methane amide, extraction Evans Blue dyestuff spends the night.

After the extraction, the methane amide of 150 μ l equal portions of each tissue sample is positioned in 96 orifice plates and uses spectrophotometer (photospectrometer) at the 610nm reading.Use GraphPad Prizm to gained data draw (OD unit).In this experiment, compound 1 reduces the seepage of LPA-inductive Evans Blue dyestuff in skin.

Embodiment 54: mouse UUO renal fibrosis model

(Harlan 20-25g), makes its ad lib and drinking-water and before the test beginning, makes it adapt at least 7 days 4 female C57BL/6 mouse of each cage stable breeding.After the adaptive phase, mouse is implemented UUO (UUO) operation or left kidney is carried out sham-operation (sham).In simple terms, carry out vertical upper left otch to expose left kidney.The location Renal artery also passes 6/0 silk thread between artery and ureter.Make this wire loop around ureter and tie a knot 3 times to guarantee complete ligation ureter.Kidney is put back to belly, sew up abdominal muscle also with the closed skin of staple.With mouse put back in its cage and in experimentation every day monitor.Every day oral administration, through intraperitoneal or subcutaneous delivery test compounds or vehicle.Route of administration and frequency are based on the previous pharmacokinetic property of confirming.After 4 days, 8 days or 14 days, utilization can suck isoflurane and put to death all animals in the UUO operation.After putting to death the blood of animal, collect kidney and half kidney is freezing and second half is fixed in 10% neutral buffered formalin so that carry out the Histological assessment of renal fibrosis with opticmicroscope (amplifying 10 times) at-80 ℃ through heart puncture collection.Use Sircol (Biocolor ltd, UK) the collagen level of analysis kidney homogenate.Also use h and E (H&E) and trichrome stain agent the fixed nephridial tissue to be dyeed and through using opticmicroscope that the collagen content that the collagen in the hepatic tissue section carries out in computer assisted density measurement and the kidney lysate is confirmed renal fibrosis.Also use the concentration of the inflammatory of commercially available elisa assay blood plasma and nephridial tissue lysate, short fibrosis and tissue injury biomarker (tissue depressant and the Type 1 plasminogen activator inhibitor-1 that comprise transforminggrowthfactor-, mucinase, metalloprotease-1).Use Graphpad prism that the gained data are drawn and definite respectively significant difference between group.

In this experiment, to compare with the untreated group, compound 1 reduces the tissue depressant and the Type 1 plasminogen activator inhibitor-1 of total kidney collagen, 1 Collagen Type VI, transforminggrowthfactor-, mucinase, metalloprotease-1.

Embodiment 55: suffer from the clinical trial among the mankind of idiopathic pulmonary fibrosis (IPF)

Purpose

The purpose of this research is compared effect and the assessment of suffering from the patient of idiopathic pulmonary fibrosis (IPF) with the compounds for treating of formula (I) for assessment and is compared the security of suffering from the patient of IPF with the compounds for treating of formula (I) with placebo with placebo.

Main outcome variable is the absolute change (representing with per-cent) by baseline to the 72 all FVC forced vital capacitys of estimating (FVC).

Less important outcome measurement comprises: the compound result of important IPF dependent event; Progresson free survival; Classification assessment by the FVC absolute change of estimating in 72 weeks of baseline to the (representing) with per-cent; By the variation of being short of breath in 72 weeks of baseline to the; Variation (representing) by the gauged carbon monoxide diffusing capacity of expectation oxyphorase (Hb) (DLco) of baseline to the 72 all lungs with per-cent; By the oxygen saturation variation of 72 weeks of baseline to the during (6MWT) tested in walking in 6 minutes; Change by the assessment of baseline to the 72 all high resolution computer tomoscans (HRCT); Change by the walking distance among baseline to the 72 all 6MWT.

Standard

The patient who is suitable for this research comprises that those satisfy the patient of following choice criteria: be diagnosed as IPF; Age is 40 years old to 80 years old; FVC>=50% predicated value; DLco>=35% predicated value; FVC or DLco≤90% predicated value; Past does not have improvement; Can 150 meters of walkings in 6 minutes and when supplemental oxygen is not more than 6L/min, keep saturation ratio>=83%.

Then it is excluded outside this research if the patient meets in the standards any one: can not accept pulmonary function test (pft); The sign that remarkable obstructive pulmonary disease or airway hyperreactivity occur; According to investigator's clinical suggestion, the expection patient possibly need and be suitable for lung transplantation in randomized 72 weeks; The active infection; Hepatopathy; In 2 years, possibly cause dead cancer or other medical conditions; Mellitus; Gestation or lactation; Substance abuse; The individual of long QT syndrome or family's medical history; Other IPF treatment; Can not take the research medicine; Giving up of other IPF test.

Patient's oral administration is given the compound (1mg/ days-1000mg/ days) of placebo or a certain amount of formula (I).Main outcome variable should be the absolute change (representing with per-cent) of the FVC that is estimated by 72 weeks of baseline to the.The patient will accept blind method research (blinded study) treatment till randomized whipper-in patient treated for 72 weeks by the randomized time.Security and efficacy data (DMC) are checked with periodicity by the data supervision council (Data Monitoring Committee), to guarantee patient safety.

After the 72nd week; Meeting the patient that PD (Progression of Disease) (POD) defines (this is defined as absolute decline per-cent >=10% of the FVC that estimates or absolute decline per-cent >=15% of the DLco that estimates) accepts also to be suitable for the IPF therapy of accepting to approve the blind method research medicine except being suitable for.The IPF therapy that allows comprises cortin, azathioprine, endoxan and N-acetyl-cysteine therapy.

Embodiment 56: parenteral pharmaceutical compositions

For preparation is suitable for the parenteral pharmaceutical compositions through injection (subcutaneous, intravenously etc.) administration, the water-soluble salt of the compound of 100mg formula (I) is dissolved in the sterilized water, mix with 10mL 0.9% sterile physiological salt solution then.Mixture is sneaked in the dosage unit form that is suitable for through drug administration by injection.

In another embodiment, mix following compositions, form injectable formulation: the compound of 1.2g formula (I), 2.0mL sodium acetate buffer solution (0.4M), HCl (1N) or NaOH (1M) (adding to appropriate pH in right amount), water (, aseptic) (adding to 20mL in right amount) through distillation.All mentioned components beyond merging dewaters also stir and if need be able to heat a little.The water that adds capacity then.

Embodiment 57: combination of oral medication

Be the pharmaceutical composition sent of preparation oral administration, the compound of 100mg formula (I) is mixed with 750mg starch.Mixture is sneaked into the oral dosage units that is used for that is suitable for oral administration such as hard gelatin capsule.

Embodiment 58: (hard lozenge) pharmaceutical composition through the hypogloeeis

Be the pharmaceutical composition (such as hard lozenge) of preparation oral delivery, the compound of 100mg formula (I) mixed with the 420mg Icing Sugar that said Icing Sugar is mixed with the light maize treacle of 1.6mL (light corn syrup), 2.4mL zero(ppm) water and 0.42mL peppermint extract.With mixture blend and pouring in the mould gently, form the lozenge that is suitable for orally administering.

Embodiment 59: quickly disintegrated sublingual tablet

Mix through compound, 44.5wt% Microcrystalline Cellulose (KG-802), 5wt% low-substituted hydroxypropyl cellulose (50 μ m) and 2wt% Magnesium Stearate and to prepare quick disintegration sublingual tablet 48.5wt% formula (I).Prepare tablet (AAPS PharmSciTech.2006 through direct compression; 7 (2): E41).Make the gross weight of the tablet of compacting maintain 150mg.(

Bioengineering AG Switzerland) mixes the low-substituted hydroxypropyl cellulose (L-HPC) of the Microcrystalline Cellulose (MCC) of the compound of the formula (I) of said amount and total amount and 2/3 amount and prepared said preparation in 4.5 minutes through using three-dimensional hand mixer.Mixing the L-HPC that end added all Magnesium Stearates (MS) in preceding 30 seconds and remained 1/3 amount.

Embodiment 60: the inhalation compositions

For preparation is used to suck the pharmaceutical composition of sending, the compound of 20mg formula (I) is mixed with 50mg Citric Acid, usp, Anhydrous Powder and 100mL 0.9% sodium chloride solution.Mixture is sneaked in the suction delivery unit (such as atomizer) that is suitable for inhalation.

Embodiment 61: the rectal gel pharmaceutical composition

Be the pharmaceutical composition sent of preparation rectum, the compound of 100mg formula (I) is mixed with 2.5g methylcellulose gum (1500mPa), 100mg methyl paraben, 5g glycerine and 100mL pure water.Then the gained gel mixture is sneaked in the rectum delivery unit (such as syringe) that is suitable for rectal administration.

Embodiment 62: the topical gel pharmaceutical composition

Be preparation medicine topical gel compsn, the pure USP that compound and 1.75g hydroxypropylcellulose, 10mL Ucar 35,10mL Isopropyl myristate and the 100mL of 100mg formula (I) is pure mixes.Then the gained gel mixture is sneaked in the container (such as pipe) that is suitable for topical.

Embodiment 63: eye solution

Be preparation medicine eye liquid composite, the compound of 100mg formula (I) mixed with 0.9g NaCl in the 100mL pure water, and use 0.2 micron filter to filter.Then the gained isotonic solution is sneaked in the ocular delivery unit (such as the eye drops container) that is suitable for dosing eyes.

Embodiment 64: nasal spray solution

Be preparation drug nasal spray solution, the compound of 10g formula (I) is mixed with 30mL 0.05M phosphate-buffered liquor (pH 4.4).Solution is positioned in the nasal administration device, and it designs to send the 100 μ l sprayss that are used for using at every turn.

Said embodiment of the application and embodiment only are used in purport that Illustrative purpose and various modifications that those skilled in the art advised or variation be included in the application and the scope and in the scope of the claim of enclosing.

Claims

1. the compound or pharmaceutically acceptable salt thereof that has the structure of formula (I),

Formula (I)

Wherein

R ¹For-CO ₂H ,-CO ₂R ^D,-CN ,-C (=O) N (R ⁹) ₂,-C (=O) NHCH ₂CH ₂SO ₃H ,-C (=O) NHSO ₂R ¹⁰, tetrazyl, or 5-oxo-2,5-dihydro-[1,2,4] oxadiazoles-3-base; R ^DBe H or C ₁-C ₄Alkyl;

R ⁴For-NR ⁷C (=O) OCH (R ⁸)-CY;

R ⁷Be H or C ₁-C ₄Alkyl;

R ⁸Be H, C ₁-C ₄Alkyl or C ₁-C ₄Fluoroalkyl;

M is 0,1 or 2;

N is 1,2,3 or 4;

P is 0,1 or 2.

2. the compound of claim 1, wherein:

R ¹For-CO ₂H ,-CO ₂R ^D,-C (=O) NHSO ₂R ¹⁰Or tetrazyl;

R ³Be H or C ₁-C ₄Alkyl;

R ⁷Be H;

R ⁸For H ,-CH ₃Or-CF ₃

R ¹⁰Be C ₁-C ₆Alkyl or through replacing or without substituted phenyl;

Each R ^ABe independently selected from F, Cl, Br, I ,-OH ,-CH ₃,-CF ₃,-OCF ₃With-OCH ₃

Each R ^BBe independently selected from F, Cl, Br, I ,-OH ,-CH ₃,-CF ₃,-OCF ₃With-OCH ₃

Each R ^CBe independently selected from F, Cl, Br, I ,-OH ,-CH ₃,-CF ₃,-OCF ₃With-OCH ₃

M is 0 or 1;

N is 1,2 or 3;

P is 0 or 1.

3. the compound of claim 2, wherein:

R ¹For-CO ₂H or-CO ₂R ^DR ^DFor H ,-CH ₃Or-CH ₂CH ₃

R ³For H ,-CH ₃Or-CH ₂CH ₃

R ⁴Be-NHC (=O) OCH (R ⁸)-CY;

R ⁸For H or-CH ₃

CY is through replacement or without substituted phenyl, and wherein if CY is through substituted phenyl, then said phenyl is substituted with 1 or 2 R ^C

4. the compound of claim 3, the compound of wherein said formula (I) has following structure:

5. the compound of claim 2, wherein:

R ¹Be-C (=O) NHSO ₂R ¹⁰

R ³For H ,-CH ₃Or-CH ₂CH ₃

R ⁸For H or-CH ₃

R ¹⁰For-CH ₃Or-CH ₂CH ₃

6. each compound in the claim 1 to 5, wherein:

R ⁴Be-NHC (=O) OCH (CH ₃)-(is through replacement or without substituted phenyl); Wherein if said phenyl is through substituted, then said phenyl is substituted with R ^CR ^CFor F, Cl ,-CH ₃Or CF ₃

N is 1.

7. each compound in the claim 1 to 5, wherein:

R ⁴For

R ⁸For-CH ₃

CY is through replacement or without substituted phenyl, and wherein if CY is through substituted phenyl, then said phenyl is substituted with 1 or 2 R ^CR ^CFor F, Cl ,-OH ,-CH ₃,-CF ₃Or-OCH ₃

N is 1.

8. the compound of claim 7, wherein:

CY is phenyl, 2-fluorophenyl, 3-fluorophenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 2-trifluoromethyl or 3-trifluoromethyl.

9. each compound in the claim 1 to 5, the compound of wherein said formula (I) has following structure:

10. the compound of claim 9, wherein:

R ¹For-CO ₂H;

11. the compound of claim 1, wherein:

R ¹For-CO ₂H ,-CO ₂R ^D,-C (=O) NHSO ₂R ¹⁰, tetrazyl or 5-oxo-2,5-dihydro-[1,2,4] oxadiazoles-3-base;

R ³Be H or C ₁-C ₄Alkyl;

R ⁷Be H;

R ⁸For H or-CH ₃

R ¹⁰Be C ₁-C ₆Alkyl or through replacing or without substituted phenyl;

CY is cyclopropyl, cyclobutyl, cyclopentyl, ring penta-1-thiazolinyl, 2-chlorine ring penta-1-thiazolinyl, cyclohexyl, hexamethylene-1-thiazolinyl, 2-chlorine hexamethylene-1-thiazolinyl, phenyl, 2-fluorophenyl, 2; 3-difluorophenyl, 2; 4-difluorophenyl, 2; 5-difluorophenyl, 2; 6-difluorophenyl, 2-chloro-phenyl-, 2; 6-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 2,4 dichloro benzene base, 2-hydroxy phenyl, 3-hydroxy phenyl, 4-hydroxy phenyl, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 2-fluoro-4-p-methoxy-phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 2-cyano-phenyl, 3-cyano-phenyl or 4-cyano-phenyl.

12. the compound of claim 11, wherein:

Each R ^ABe independently selected from F, Cl ,-CH ₃,-CF ₃,-OH ,-OCF ₃With-OCH ₃

Each R ^BBe independently selected from F, Cl ,-CH ₃,-CF ₃,-OH ,-OCF ₃With-OCH ₃

M is 0 or 1;

N is 1;

P is 0 or 1.

13. the compound or pharmaceutically acceptable salt thereof of claim 1 is selected from:

1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid (compound 1);

1-{4 '-[4-(1-cyclohexyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid (compound 2);

1-{4 '-[3-methyl-4-((R)-1-neighbour-tolyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid (compound 3);

1-[4 '-(4-benzyl oxygen base carbonylamino-3-methyl-isoxazole-5-bases)-biphenyl-4-yl]-cyclopropane-carboxylic acid (compound 4);

(S)-1-{4 '-[4-(1-cyclopropyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid (compound 5);

(R)-1-{4 '-[4-(1-cyclopropyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid (compound 6);

1-[4 '-(4-cyclo propyl methoxy carbonylamino-3-methyl-isoxazole-5-bases)-biphenyl-4-yl]-cyclopropane-carboxylic acid (compound 7);

1-(4 '-4-[(R)-1-(2-chloro-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 8);

1-(4 '-3-methyl-4-[(R)-1-(2-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 9);

1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-NSC 4535 (compound 10);

1-{4 '-[3-methyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-Cyclopentane carboxylic acid (compound 11);

1-(4 '-{ 4-[1-(2-methoxyl group-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 12);

1-(4 '-{ 3-methyl-4-[1-(4-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 13);

1-(4 '-{ 3-methyl-4-[1-(4-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 14);

1-(4 '-{ 4-[1-(3-cyanic acid-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 15);

1-{4 '-[3-methyl-4-((R)-1-is right-and tolyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid (compound 16);

1-{4 '-[3-methyl-4-(between (R)-1--tolyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid (compound 17);

1-(4 '-4-[(R)-1-(4-cyanic acid-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 18);

1-(4 '-4-[(R)-1-(2-cyanic acid-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 19);

1-{4 '-[4-((R)-1-cyclobutyl-ethoxy carbonyl is amino)-3-methyl-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid (compound 20);

1-(4 '-{ 4-[1-(2-chloro-hexamethylene-1-thiazolinyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 21);

1-(4 '-3-methyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 22);

1-(4 '-4-[(R)-1-(3-methoxyl group-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 23);

1-(4 '-4-[(R)-1-(4-methoxyl group-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 24);

1-(4 '-{ 4-[1-(3-bromo-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 25);

1-(4 '-{ 4-[1-(3-chloro-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 26);

1-{4 '-[3-methyl-4-((S)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid (compound 27);

1-(4 '-{ 4-[1-(3-hydroxyl-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 28);

1-{4 '-[3-ethyl-4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid (compound 29);

1-(4 '-3-ethyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 30);

1-(3 '-methoxyl group-4 '-3-methyl-4-[(R)-1-(3-trifluoromethyl-phenyl)-ethoxy carbonyl is amino]-isoxazole-5-bases }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 31);

1-(4 '-4-[(R)-1-(3,5-two bromo-phenyl)-ethoxy carbonyl is amino]-3-methyl-isoxazole-5-base }-biphenyl-4-yl)-cyclopropane-carboxylic acid (compound 32);

1-{4 '-[4-((R)-1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid (compound 33);

1-{4 '-[3-methyl-4-(1-phenyl-ethoxy carbonyl is amino)-isoxazole-5-bases]-biphenyl-4-yl }-cyclopropane-carboxylic acid (compound 34);

5-[4 '-(1-methylsulfonyl aminocarboxyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-phenyl-ethyl ester (compound 35);

5-[4 '-(1-benzenesulfonyl aminocarboxyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-phenyl-ethyl ester (compound 36);

5-[4 '-(1-cyanic acid-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-phenyl-ethyl ester (compound 37);

(3-methyl-5-{4 '-[1-(5-oxo-2, the 5-dihydro-[1,2,4] oxadiazole-3-yls)-cyclopropyl]-biphenyl-4-yl }-isoxazole-4-bases)-carboxylamine (R)-1-phenyl-ethyl ester (compound 38);

(3-methyl-5-{4 '-[1-(1H-tetrazolium-5-yl)-cyclopropyl]-biphenyl-4-yl }-isoxazole-4-bases)-carboxylamine (R)-1-phenyl-ethyl ester (compound 39);

5-[4 '-(1-methylsulfonyl aminocarboxyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester (compound 40);

5-[4 '-(1-methylsulfonyl aminocarboxyl-cyclopropyl)-3-methoxyl group-biphenyl-4-yl]-3-methyl-isoxazole-4-bases }-carboxylamine (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester (compound 41).

14. pharmaceutical composition, it comprises in the claim 1 to 13 of treating significant quantity each compound or pharmaceutically acceptable salt thereof.

15. the pharmaceutical composition of claim 14, wherein:

(a) said pharmaceutical composition is used for intravenous injection, subcutaneous injection, oral administration, suction, intranasal administration, topical, dosing eyes or ear's administration by preparation; Or

(b) said pharmaceutical composition is tablet, pill, capsule, liquid, inhalation, nasal spray solution, suppository, suspensoid, gelifying agent, colloid, dispersion agent, suspensoid, solution, emulsion, ointment, lotion, eye drops or ear drop.

16. the method for treatment mammalian cancer, it comprises in the claim 1 to 13 of the Mammals drug treatment significant quantity that these needs are arranged each compound or pharmaceutically acceptable salt thereof.

17. the method for treatment or prevention mammalian hair fiberization, it comprises in the claim 1 to 13 of the Mammals drug treatment significant quantity that these needs are arranged each compound or pharmaceutically acceptable salt thereof.

18. the method for treatment or prevention Mammals following disease: pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute injury of kidney, chronic nephropathy, hepatic fibrosis, fibrosis of skin, intestines fibrosis, breast cancer, carcinoma of the pancreas, ovarian cancer, prostate cancer, glioblastoma, osteocarcinoma, colorectal carcinoma, intestinal cancer, head and neck cancer, melanoma, multiple myeloma, lymphocytic leukemia, cancer pain, metastases, transplant organ repulsion, scleroderma, eye fibrosis, AMD (AMD), diabetic retinopathy, collagen vascular diseases, atherosclerosis, Raynaud's phenomenon or neuropathic pain, it comprises in the claim 1 to 13 of the Mammals drug treatment significant quantity that these needs are arranged each compound or pharmaceutically acceptable salt thereof.